Quinolines and nitrogenated derivative thereof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents

ABSTRACT

Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a National Stage Application filed under 35U.S.C.§371 of PCT/EP02/00587, filed on Jan. 22, 2002, which claimspriority of GB Application No. 0101577.5, filed Jan. 22, 2001.

This invention relates to novel compounds, compositions containing themand their use as antibacterials.

WO99/37635, WO00/21948, WO00/21952, WO00/43383, WO00/78748, WO01/07432and WO01/07433 disclose piperidine and piperazine derivatives havingantibacterial activity.

We have now found a novel group of aminopiperidines which haveantibacterial activity.

This invention provides a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof:

wherein:

-   one of Z¹, Z², Z³, Z⁴ and Z⁵ is N, one is CR^(1a) and the remainder    are CH, or one of Z¹, Z², Z³, Z⁴ and Z⁵ is CR^(1a) and the remainder    are CH;-   R¹ and R^(1a) are independently hydrogen; hydroxy; (C₁₋₆)alkoxy    optionally substituted by (C₁₋₆)alkoxy, amino, piperidyl, guanidino    or amidino any of which is optionally N-substituted by one or two    (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups, CONH₂, hydroxy,    (C₁₋₆)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio,    aryloxy, acylthio, acyloxy or (C₁₋₆)alkylsulphonyloxy;    (C₁₋₆)alkoxy-substituted(C₁₋₆)alkyl; halogen; (C₁₋₆)alkyl;    (C₁₋₆)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido;    acyl; acyloxy; acylthio; (C₁₋₆)alkylsulphonyl;    (C₁₋₆)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino,    piperidyl, guanidino or amidino group optionally N-substituted by    one or two (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups;-   or when Z⁵ is CR^(1a), R^(1a) may instead be cyano, hydroxymethyl or    carboxy; provided that when none of Z¹, Z², Z³, Z⁴ and Z⁵ is N, then    R¹ is not hydrogen;-   R² is hydrogen, or (C₁₋₄)alkyl or (C₂₋₄)alkenyl optionally    substituted with 1 to 3 groups selected from:-   amino optionally substituted by one or two (C₁₋₄)alkyl groups;    carboxy; (C₁ ₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;    (C₂₋₄)alkenyloxycarbonyl; (C₂ ₋₄)alkenylcarbonyl; aminocarbonyl    wherein the amino group is optionally substituted by hydroxy,    (C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl,    (C₂₋₄)alkenyl, (C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₄)alkenylsulphonyl, (C₁ ₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,    (C₂₋₄)alkenyloxycarbonyl or (C₂ ₋₄)alkenylcarbonyl; cyano;    tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;    3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;    tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally    substituted by R¹⁰; 5-oxo-1,2,4-oxadiazol-3-yl; halogen;    (C₁₋₄)alkylthio; trifluoromethyl; hydroxy optionally substituted by    (C₁ ₋₄)alkyl, (C₂₋₄)alkenyl, (C₁₋₄)alkoxycarbonyl,    (C₁₋₄)alkylcarbonyl, (C₂ ₋₄)alkenyloxycarbonyl,    (C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl; (C₂    ₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino group    is optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl;-   R³ is hydrogen; or-   R³ is in the 2-, 3- or 4-position and is:-   carboxy, (C₁₋₆)alkoxycarbonyl; (C₂₋₆)alkenyloxycarbonyl;    aminocarbonyl wherein the amino group is optionally substituted by    hydroxy, (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl,    (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl, (C₁ ₋₆)alkylcarbonyl,    (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally    further substituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,    aminocarbonyl(C₁₋₆)alkyl or (C₂ ₋₆)alkenyl; cyano; tetrazolyl;    2-oxo-oxazolidinyl optionally substituted by R¹⁰;    3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;    tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally    substituted by R¹⁰; or 5-oxo-1,2,4-oxadiazol-3-yl; or-   (C₁₋₄)alkyl or ethenyl optionally substituted with any of the    substituents listed above for R³ and/or 0 to 2 groups R¹²    independently selected from:

halogen; (C₁₋₆)alkylthio; trifluoromethyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl;hydroxy optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylcarbonyl or (C₂ ₋₆)alkenylcarbonyl; amino optionally mono- ordisubstituted by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyland optionally further substituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; oxo; (C₁ ₋₆)alkylsulphonyl;(C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or when R³ isin the 3-position, hydroxy optionally substituted as described above;

-   in addition when R³ is disubstituted with a hydroxy or amino    containing substituent and carboxy containing substituent these may    together form a cyclic ester or amide linkage, respectively;-   R⁴ is a group —U—R⁵ where-   U is selected from CO, SO₂ and CH₂ and-   R⁵ is an optionally substituted bicyclic carbocyclic or heterocyclic    ring system (A):

containing up to four heteroatoms in each ring in which

ring (a) is aromatic and ring (b) is non-aromatic;

X¹ is C or N;

X² is N, NR¹³, O, S(O)_(x), CO or CR¹⁴;

X³ and X⁵ are independently N or C;

Y¹ is a 0 to 4 atom linker group each atom of which is independentlyselected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴;

Y² is a 2 to 6 atom linker group, each atom of Y² being independentlyselected from N, NR¹³, O, S(O)_(x), CO, CR¹⁴ and CR¹⁴R¹⁵;

-   each of R¹⁴ and R¹⁵ is independently selected from: H;    (C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy;    halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl;    formyl; (C₁₋₄)alkylcarbonyl; (C₂₋₄)alkenyloxycarbonyl;    (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;    (C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;    mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino or    aminocarbonyl optionally substituted as for corresponding    substituents in R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or    aminosulphonyl wherein the amino group is optionally mono- or    di-substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; aryl;    aryl(C₁₋₄)alkyl; aryl(C₁₋₄)alkoxy;

each R¹³ is independently H; trifluoromethyl; (C₁₋₄)alkyl optionallysubstituted by hydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo ortrifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl; arylcarbonyl;heteroarylcarbonyl; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl;(C₁₋₆)alkylsulphonyl; or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,(C₂₋₄)alkenyloxycarbonyl, (C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or(C₂₋₄)alkenyl and optionally further substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl;

-   each x is independently 0, 1 or 2-   n is 0 and AB is NR¹¹ CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NHR¹¹SO₂, CR⁶R⁷—SO₂ or    CR⁶R⁷—CR⁸R⁹;-   or n is 1 and AB is NR¹¹ CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NR¹¹SO₂, CONR¹¹,    CR⁶R⁷—CR⁸R⁹, O—CR⁸R⁹ or NR¹¹—CR⁸R⁹;-   wherein CR⁶R⁷ is CH₂, CHOH, CH(NH₂), C(Me)(OH) or CH(Me) and CR⁸R⁹    is CH₂;-   R¹⁰ is selected from (C₁₋₄)alkyl; (C₂₋₄)alkenyl and aryl any of    which may be optionally substituted by a group R¹² as defined above,    carboxy; aminocarbonyl wherein the amino group is optionally    substituted by hydroxy. (C₁₋₆)alkyl, (C₂₋₆)alkenyl.    (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,    (2-6)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,    (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally    further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; and-   R¹¹ is hydrogen; trifluoromethyl, (C₁₋₆)alkyl; (C₂₋₆)alkenyl;    (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; or aminocarbonyl wherein    the amino group is optionally substituted by (C₁₋₆)alkoxycarbonyl.    (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,    (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionally    further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl,    or where one of R³ and R⁶ or R⁷ contains a carboxy group and the    other contains a hydroxy or amino group they may together form a    cyclic ester or amide linkage.

This invention also provides a method of treatment of bacterialinfections in mammals, particularly in man, which method comprises theadministration to a mammal in need of such treatment an effective amountof a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for use in the treatment of bacterial infections in mammals.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable derivativethereof, and a pharmaceutically acceptable carrier.

Preferably Z⁵ is CH or N, Z³ is CH or CF and Z¹, Z² and Z⁴ are each CH,or Z¹ is N, Z³ is CH or CF and Z², Z⁴ and Z⁵ are each CH.

When R¹ or R^(1a) is substituted alkoxy it is preferably (C₂₋₆)alkoxysubstituted by optionally N-substituted amino, guanidino or amidino, or(C₁₋₆)alkoxy substituted by piperidyl. Suitable examples of R¹ andR^(1a) alkoxy include methoxy, trifluoromethoxy, n-propyloxy,iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy,aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimidopentyloxy or 2-aminocarbonylprop-2-oxy.

Preferably R¹ and R^(1a) are independently methoxy, amino(C₃₋₅)alkyloxy,guanidino(C₃₋₅)alkyloxy, piperidyl(C₃₋₅)alkyloxy, nitro or fluoro; morepreferably methoxy, amino(C₃₋₅)alkyloxy or guanidino(C₃₋₅)alkyloxy. Mostpreferably R¹ is methoxy and R^(1a) is H or when Z³ is CR^(1a) it may beC—F.

When Z⁵ is CR^(1a), R^(1a) is preferably hydrogen, cyano, hydroxymethylor carboxy, most preferably hydrogen.

Preferably n is 0.

R² is preferably hydrogen; (C₁₋₄)alkyl substituted with carboxy,optionally substituted hydroxy, optionally substituted aminocarbonyl,optionally substituted amino or (C₁₋₄)alkoxycarbonyl; or (C₂₋₄)alkenylsubstituted with (C₁₋₄)alkoxycarbonyl or carboxy. More preferred groupsfor R² are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl, mostpreferably hydrogen.

Preferred examples of R³ include hydrogen; optionally substitutedhydroxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄) alkyl; ethenyl; optionallysubstituted 1-hydroxy-(C₁₋₄) alkyl; optionally substitutedaminocarbonyl; carboxy(C₁₋₄)alkyl; optionally substitutedaminocarbonyl(C₁₋₄)alkyl; cyano(C₁₋₄)alkyl; optionally substituted2-oxo-oxazolidinyl and optionally substituted2-oxo-oxazolidinyl(C₁₋₄alkyl). More preferred R³ groups are hydrogen;CONH₂; 1-hydroxyalkyl e.g. CH₂OH, CH(OH)CH₂CN; CH₂CO₂H; CH₂CONH₂;CONHCH₂CONH₂; 1,2-dihydroxyalkyl e.g. CH(OH)CH₂OH; CH₂CN;2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C₁₋₄alkyl). Mostpreferably R³ is hydrogen.

R³ is preferably in the 3- or 4-position.

When R³ is in the 3-position, preferably it is trans to (NR²)R⁴.

When R³ and R⁶, R⁷, R⁸ or R⁹ together form a cyclic ester or amidelinkage, it is preferred that the resulting ring is 5-7 membered.

Preferably n=0.

When A is CH(OH) the R-stereochemistry is preferred.

Preferably A is NH, NCH₃, CH₂, CHOH, CH(NH₂), C(Me)(OH) or CH(Me).

Preferably B is CH₂ or CO.

Preferably A-B is CHOH—CH₂, NR¹¹—CH₂ or NR¹¹—CO.

Particularly preferred are those compounds where n=0, A is NH and B isCO, or A is CHOH and B is CH₂, when more preferably A is the R-isomer ofCHOH.

Preferably R¹¹ is hydrogen or (C₁₋₄)alkyl e.g. methyl, more preferablyhydrogen.

U is most preferably CH₂.

Preferably in the heterocyclic ring (A) Y² has 3–5 atoms, morepreferably 4 atoms, including NR¹³, O or S bonded to X⁵ and NHCO bondedvia N to X³, or O or NH bonded to X³. The ring (a) preferably containsaromatic nitrogen, and more preferably ring (a) is pyridine. Examples ofrings (A) include optionally substituted:1,1,3-trioxo-1,2,3,4-tetrahydrol l⁶-benzo[1,4]thiazin-3-one-6-yl,benzo[1,3]dioxol-5-yl, 4H-benzo[1,4]oxazin-3-one-6-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, 2-oxo-2,3-dihydro-benzooxazol-6-yl,3-substituted-3H-benzooxazol-2-one-6-yl,3-substituted-3H-benzooxazole-2-thione-6-yl,3-substituted-3H-benzothiazol-2-one-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl),4H-benzo[1,4]thiazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl),4H-benzo[1,4]oxazin-3-one-7-yl,4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl,5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl,benzo[1,3]dioxol-5-yl, 1H-pyrido[2,3-b][1,4]thiazin-2-one-7-yl(2-oxo-2,3-dihydro-1H-pyrido[2,3-b]thiazin-7-yl),2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,2-oxo-2,3-dihydro-1H-pyrido[3,4-b]thiazin-7-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,2,3-1,4]dioxino[2,3-b]pyridin-7-yl,3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,3,4-dihydro-1H-quinolin-2-one-7-yl,3,4-dihydro-1H-quinoxalin-2-one-7-yl,6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl,5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl,2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl.

R¹³ is preferably H if in ring (a) or in addition (C₁₋₄)alkyl such asmethyl or isopropyl when in ring (b). More preferably, in ring (b) R¹³is H when NR¹³ is bonded to X³ and (C₁-14)alkyl when NR¹³ is bonded toX⁵.

R¹⁴ and R¹⁵ are preferably independently selected from hydrogen, halo,hydroxy, (C₁₋₄)alkoxy, trifluoromethoxy, nitro, cyano, aryl(C₁₋₄)alkoxyand (C₁₋₄)alkylsulphonyl. More preferably R¹⁵ is hydrogen.

More preferably each R¹⁴ is selected from hydrogen, chloro, fluoro,hydroxy, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano andmethylsulphonyl. Most preferably R¹⁴ is selected from hydrogen, fluorineor nitro. Preferably 0–3 groups R¹⁴ are substituents other thanhydrogen. Preferably when R¹⁴ is not hydrogen, X⁴ is CR¹⁴ and/or CR¹⁴ isa component of Y².

Most preferred groups R⁵ include:

2,3-dihydro-benzo[1,4]dioxin-6-yl

benzo[1,3]dioxol-5-yl

2,2-difluoro-benzo[1,3]dioxol-5-yl

4H-benzo[1,4]oxazin-3-one-6-yl

4H-benzo[1,4]thiazin-3-one-6-yl

7-fluoro-4H-benzo[1,4]oxazin-3-one-6-yl

6-chloro-benzo[1,3]dioxol-5-yl

5-fluoro-3-methyl-3H-benzooxazol-2-one-6-yl

2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl

3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl

7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.

When used herein, the term “alkyl” includes groups having straight andbranched chains, for instance, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl and hexyl. The term‘alkenyl’ should be interpreted accordingly.

Halo or halogen includes fluoro, chloro, bromo and iodo.

Haloalkyl moieties include 1-3 halogen atoms.

Unless otherwise defined, the term “heterocyclic” as used hereinincludes optionally substituted aromatic and non-aromatic, single andfused, rings suitably containing up to four hetero-atoms in each ringselected from oxygen, nitrogen and sulphur, which rings may beunsubstituted or C-substituted by, for example, up to three groupsselected from (C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl;halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl;(C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; optionally substituted aryl, aryl(C₁₋₄)alkyl oraryl(C₁₋₄)alkoxy and oxo groups.

Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ringatoms. A fused heterocyclic ring system may include carbocyclic ringsand need include only one heterocyclic ring.

Compounds within the invention containing a heterocyclyl group may occurin two or more tautometric forms depending on the nature of theheterocyclyl group; all such tautomeric forms are included within thescope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include H; trifluoromethyl; (C₁₋₄)alkyloptionally substituted by hydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, haloor trifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl;(C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl;or aminocarbonyl wherein the amino group is optionally substituted by(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and optionallyfurther substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl.

When used herein the term “aryl”, includes optionally substituted phenyland naphthyl.

Aryl groups may be optionally substituted with up to five, preferably upto three, groups selected from (C₁₋₄)alkylthio; halo;carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl;(C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; phenyl, phenyl(C₁₋₄)alkyl or phenyl(C₁₋₄)alkoxy

The term “acyl” includes formyl and (C₁₋₆)alkylcarbonyl group.

Preferred compounds of formula (I) include:

-   (R)-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,-   (R)-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol,-   (R)-2-{4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,-   6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-one,-   6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one,-   7-Fluoro-6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-one,-   6-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-one,-   (R)-2-{4-(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol,-   6-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]thiazin-3-one,-   7-Bromo-6-{{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]thiazin-3-one,-   7-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-1H-pyrido[3,4-b][1,4]thiazin-2-one-   (R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,-   (R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol,-   3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid    {1-[(R)-2-hydroxy-2-6-methoxy[1,5]naphthyridin-4-yl)ethyl]piperidin-4-yl}amide,    and pharmaceutically acceptable derivatives thereof.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or pharmaceutically acceptable derivative thereof.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable derivatives.

Pharmaceutically acceptable derivatives of the above-mentioned compoundsof formula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, ororganic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic,p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid ortartaric acids. Compounds of formula (I) may also be prepared as theN-oxide. Compounds of formula (I) having a free carboxy group may alsobe prepared as an in vivo hydrolysable ester. The invention extends toall such derivatives.

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester-forming groups include those forming esters which break downreadily in the human body to leave the parent acid or its salt. Suitablegroups of this type include those of part formulae (i), (ii), (iii),(iv) and (v):

wherein R^(a) is hydrogen, (C₁₋₆) alkyl, (C₃₋₇) cycloalkyl, methyl, orphenyl, R^(b) is (C₁₋₆) alkyl, (C₁₋₆) alkoxy, phenyl, benzyl, (C₃₋₇)cycloalkyl, (C₃₋₇) cycloalkyloxy, (C₁₋₆) alkyl (C₃₋₇) cycloalkyl,1-amino (C₁₋₆) alkyl, or 1-(C₁₋₆ alkyl)amino (C₁₋₆) alkyl; or R^(a) andR^(b) together form a 1,2-phenylene group optionally substituted by oneor two methoxy groups; R^(c) represents (C₁₋₆) alkylene optionallysubstituted with a methyl or ethyl group and R^(d) and R^(e)independently represent (C₁₋₆) alkyl; R^(f) represents (C₁₋₆) alkyl;R^(g) represents hydrogen or phenyl optionally substituted by up tothree groups selected from halogen, (C₁₋₆) alkyl, or (C₁₋₆) alkoxy; Q isoxygen or NH; R^(h) is hydrogen or (C₁₋₆) alkyl; R^(i) is hydrogen,(C₁₋₆) alkyl optionally substituted by halogen, (C₂₋₆) alkenyl, (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; or R^(h) and R^(i) together form(C₁₋₆) alkylene; R^(j) represents hydrogen, (C₁₋₆) alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents (C₁₋₈) alkyl, (C₁₋₈) alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, forexample, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl,pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl,1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl;(C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such asethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl andpropoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especiallydi(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl,dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;2-((C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysableester-forming group is that of the formula:

wherein R^(k) is hydrogen, C₁₋₆ alkyl or phenyl.

R is preferably hydrogen.

Compounds of formula (I) may also be prepared as the correspondingN-oxides.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such forms, inparticular the pure isomeric forms. For example the invention includescompound in which an A-B group CH(OH)—CH₂ is in either isomericconfiguration, the R-isomer is preferred. The different isomeric formsmay be separated or resolved one from the other by conventional methods,or any given isomer may be obtained by conventional synthetic methods orby stereospecific or asymmetric syntheses.

In a further aspect of the invention there is provided a process forpreparing compounds of formula (I), and pharmaceutically acceptablederivatives thereof, which process comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein n is as defined in formula (I); Z^(1′), Z^(2′); Z^(3′) Z^(4′),Z^(5′), R^(1′) and R^(3′) are Z¹, Z², Z³, Z⁴, Z⁵, R¹, and R³ as definedin formula (I) or groups convertible thereto;

-   Q¹ is NR^(2′)R^(4′) or a group convertible thereto wherein R^(2′)    and R⁴ are R² and R⁴ as defined in formula (I) or groups convertible    thereto and Q² is H or R^(3′) or Q¹ and Q² together form an    optionally protected oxo group;-   (i) X is A′-COW, Y is 1 and n is 0;-   (ii) X is CR⁶═CR⁸R⁹, Y is H and n is 0;-   (iii) X is oxirane, Y is H and n is 0;-   (iv) X is N═C═O and Y is H and n is 0;-   (v) one of X and Y is CO₂R^(y) and the other is CH₂CO₂P^(x);-   (vi) X is CHR⁶R⁷ and Y is C(═O)R⁹;-   (vii) X is CR⁷═PR^(z) ₃ and Y is C(═O)R⁹ and n=1;-   (viii) X is C(═O)R⁷ and Y is CR⁹═PR^(z) ₃ and n−1;-   (ix) Y is COW and X is NHR^(11′), NCO or NR^(11′)COW and n=0 or 1 or    when n−1 X is COW and Y is NR^(11′), NCO or NR^(11′)COW;-   (x) X is NHR^(11′) and Y is C(═O)R⁸ and n=1;    -   (xi) X is NHR^(11′) and Y is CR⁸R⁹W and n=1;    -   (xii) X is NR¹¹′COCH₂W or NR^(11′)SO₂CH₂W and Y is H and n=0;    -   (xiii) X is CR⁶R⁷SO₂W and Y is H and n=0;    -   (xiv) X is W or OH and Y is CH₂OH and n is 1;    -   (xv) X is NHR^(11′) and Y is SO₂W or X is NR^(11′)SO₂W and Y is        H, and n is 0;    -   (xvi) X is W and Y is CONHR^(11′);        in which W is a leaving group, e.g. halo or imidazolyl; R^(x)        and R^(y) are (C₁₋₆)alkyl; R^(z) is aryl or (C₁₋₆)alkyl; A′ and        NR^(11′) are A and NR¹¹ as defined in formula (I), or groups        convertible thereto; and oxirane is:

wherein R⁶, R⁸ and R⁹ are as defined in formula (I);

-   and thereafter optionally or as necessary converting Q¹ and Q², to    NR^(2′)R^(4′)—; converting A′, Z^(1′), Z^(2′), Z^(3′), Z^(4′),    Z^(5′), R^(1′), R^(2′), R^(3′), R^(4′) and NR^(11′); to A, Z¹, Z²,    Z³, Z⁴, Z⁵, R¹, R², R³, R⁴ and NR¹¹; converting A-B to other A-B,    interconverting R¹, R², R³ and/or R⁴, and/or forming a    pharmaceutically acceptable derivative thereof.

Process variant (i) initially produces compounds of formula (I) whereinA-B is A′-CO.

Process variant (ii) initially produces compounds of formula (I) whereinA-B is CHR⁶—CR⁸R⁹.

Process variant (iii) initially produces compounds of formula (I)wherein A-B is CR⁶(OH)—CR⁸R⁹.

Process variant (iv) initially produces compounds of formula (I) whereA-B is NH—CO.

Process variant (v) initially produces compounds of formula (I) whereinA-B is CO—CH₂ or CH₂—CO.

Process variant (vi) initially produces compounds of formula (I) whereinA-B is CR⁶R⁷—CR⁹OH.

Process variant (vii) and (viii) initially produce compounds of formula(I) wherein A-B is CR⁷═CR⁹.

Process variant (ix) initially produces compounds of formula (I) whereA-B is CO—NR¹¹ or NR¹¹—CO.

Process variant (x) initially produces compounds of formula (I) whereinA-B is NR¹¹—CHR⁸.

Process variant (xi) initially produces compounds of formula (I) whereinA-B is NR^(11′)—CR⁸R⁹.

Process variant (xii) initially produces compounds of formula (I) whereA-B is NR^(11′)—CO or NR^(11′)—SO₂ and n=1.

Process variant (xiii) initially produces compounds of formula (I) whereA-B is CR⁶R⁷—SO₂.

Process variant (xiv) initially produces compounds of formula (I)wherein A-B is O—CH₂.

Process variant (xv) initially produces compounds where AB is NR¹¹SO₂.

Process variant (xvi) initially produces compounds of formula (I) whereA-B is NR^(11′)—CO.

In process variants (i) and (ix) the reaction is a standard amide orurea formation reaction involving e.g.:

-   1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed    anhydride, active ester, O-acyl-isourea or other species), and    treatment with an amine (Ogliaruso, M. A.; Wolfe, J. F. in The    Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The    Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp    442–8; Beckwith, A. L. J. in The Chemistry of Functional Groups (Ed.    Patai, S.) Suppl. B: The Chemistry of Amides (Ed. Zabricky, J.)    (John Wiley and Sons, 1970), p 73 ff. The acid and amine are    preferably reacted in the presence of an activating agent such as    1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or    1-hydroxybenzotriazole (HOBT) or    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate (HATU); or-   2. The specific methods of:-   a. in situ conversion of an acid into the amine component by a    modified Curtius reaction procedure (Shioiri, T., Murata, M.,    Hamada, Y., Chem. Pharm. Bull. 1987, 35, 2698)-   b. in situ conversion of the acid component into the acid chloride    under neutral conditions (Villeneuve, G. B.; Chan, T. H.,    Tetrahedron. Lett. 1997, 38, 6489).

A′ may be, for example, protected hydroxymethylene.

The process variant (ii) is a standard addition reaction using methodswell known to those skilled in the art. The process is preferablycarried out in a polar organic solvent e.g. acetonitrile in the presenceof an organic base e.g. triethylamine.

In process variant (iii) the coupling may be effected in a suitablesolvent such as acetonitrile or dimethylformamide at room temperature inthe presence of one equivalent of lithium perchlorate as catalyst(general method of J. E. Chateauneuf et al, J. Org. Chem., 56,5939–5942, 1991) or more preferably with ytterbium triflate indichloromethane. In some cases an elevated temperature such as 40–70° C.may be beneficial. Alternatively, the piperidine may be treated with abase, such as one equivalent of butyl lithium, and the resulting saltreacted with the oxirane in an inert solvent such as tetrahydrofuran,preferably at an elevated temperature such as 80° C. Use of a chiralepoxide will afford single diastereomers. Alternatively, mixtures ofdiastereomers may be separated by preparative HPLC or by conventionalresolution through crystallisation of salts formed from chiral acids.

The process variant (iv) is a standard urea formation reaction from thereaction of an isocyanate with an amine and is conducted by methods wellknown to those skilled in the art (for example see March, J; AdvancedOrganic Chemistry, Edition 3 (John Wiley and Sons, 1985), p802–3). Theprocess is preferably carried out in a polar solvent such asN,N-dimethylformamide.

In process variant (v) the process is two step: firstly a condensationusing a base, preferably sodium hydride or alkoxide, sodamide, alkyllithium or lithium dialkylamide, preferably in an aprotic solvent e.g.ether, THF or benzene; secondly, hydrolysis using an inorganic acid,preferably HCl in aqueous organic solvent at 0–100° C. Analogous routesare described in DE330945, EP31753, EP53964 and H. Sargent, J. Am. Chem.Soc. 68, 2688–2692 (1946). Similar Claisen methodology is described inSoszko et. al., Pr. Kom. Mat. Przyr. Poznan. Tow. Przj. Nauk., (1962),10, 15.

In process variant (vi) the reaction is carried out in the presence of abase, preferably organometallic or metal hydride e.g. NaH, lithiumdiisopropylamide or NaOEt, preferably in an aprotic solvent, preferablyTHF, ether or benzene at −78 to 25° C. (analogous process in Gutswilleret al. (1978) J. Am. Chem. Soc. 100, 576).

In process variants (vii) and (viii) if a base is used it is preferablyNaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt,sodamide or lithium dialkylamide e.g. di-isopropylamide. An analogousmethod is described in U.S. Pat. No. 3,989,691 and M. Gates et. al.(1970) J. Amer. Chem. Soc., 92, 205, as well as Taylor et al. (1972)JACS 94, 6218.

In process variant (x) where Y is CHO the reaction is a standardreductive alkylation using, e.g., sodium borohydride or sodiumtriacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents forOrganic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p4649).

The process variant (xi) is a standard alkylation reaction well known tothose skilled in the art, for example where an alcohol or amine istreated with an alkyl halide in the presence of a base (for example seeMarch, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons,1985), p364–366 and p342–343). The process is preferably carried out ina polar solvent such as N,N-dimethylformamide

In process variant (xii) the reaction is an alkylation, examples ofwhich are described in J. Med. chem. (1979) 22(10) 1171–6. The compoundof formula (IV) maybe prepared from the corresponding compound where Xis NHR^(11′) by acylation with an appropriate derivative of the acidWCH₂COOH such as the acid chloride or sulphonation with an appropriatederivative of the sulphonic acid WCH₂SO₃H such as the sulphonylchloride.

In process variant (xiii) the reaction is a standard sulphonamideformation reaction well known to those skilled in the art. This may bee.g. the reaction of a sulphonyl halide with an amine.

In process variant (xiv) where X is W such as halogen,methanesulphonyloxy or trifluoromethanesulphonyloxy, the hydroxy groupin Y is preferably converted to an OM group where M is an alkali metalby treatment of an alcohol with a base. The base is preferably inorganicsuch as NaH, lithium diisopropylamide or sodium. Where X is OH, thehydroxy group in Y is activated under Mitsunobu conditions (Fletcher et.al. J Chem Soc. (1995), 623). Alternatively the X═O and Y═CH₂OH groupscan be reacted directly by activation with dichlorocarbodiimide (DCC)(Chem. Berichte 1962, 95, 2997 or Angewante Chemie 1963 75, 377).

In process variant (xv) the reaction is conducted in the presence of anorganic base such as triethylamine or pyridine such as described byFuhrman et. al., J. Amer. Chem. Soc.; 67, 1245, 1945. The X═NR¹¹′SO₂W orY═SO₂W intermediates can be formed from the requisite amine e.g. byreaction with SO₂Cl₂ analogously to the procedure described by the sameauthors Fuhrman et. al., J. Amer. Chem. Soc.; 67, 1245, 1945.

In process variant (xvi) the leaving group W is preferably chloro, bromoor iodo or trifluoromethylsulphonyloxy and the reaction is the palladiumcatalysed process known as the “Buchwald” reaction (J. Yin and S. L.Buchwald, Org. Lett., 2000, 2, 1101).

Reduction of a carbonyl group A or B to CHOH can be readily accomplishedusing reducing agents well known to those skilled in the art, e.g.sodium borohydride in aqueous ethanol or lithium aluminium hydride inethereal solution. This is analogous to methods described in EP53964,U.S. Pat. No. 384,556 and J. Gutzwiller et al, J. Amer. Chem. Soc.,1978, 100, 576.

The carbonyl group A or B may be reduced to CH₂ by treatment with areducing agent such as hydrazine in ethylene glycol, at e.g. 130–160°C., in the presence of potassium hydroxide.

Reaction of a carbonyl group A or B with an organometallic reagentyields a group where R⁶ or R⁸ is OH and R⁷ or R⁹ is alkyl.

A hydroxy group on A or B may be oxidised to a carbonyl group byoxidants well known to those skilled in the art, for example, manganesedioxide, pyridinium chlorochromate or pyridinium dichromate.

A hydroxyalkyl A-B group CHR⁷CR⁹OH or CR⁷(OH)CHR⁹ may be dehydrated togive the group CR⁷═CR⁹ by treatment with an acid anhydride such asacetic anhydride.

Methods for conversion of CR⁷═CR⁹ by reduction to CHR⁷CHR⁹ are wellknown to those skilled in the art, for example using hydrogenation overpalladium on carbon as catalyst. Methods for conversion of CR⁷═CR⁹ togive the A-B group CR⁷(OH)CHR⁹ or CHR⁷CR⁹OH are well known to thoseskilled in the art for example by epoxidation and subsequent reductionby metal hydrides, hydration, hydroboration or oxymercuration.

An amide carbonyl group may be reduced to the corresponding amine usinga reducing agent such as lithium aluminium hydride.

A hydroxy group in A or B may be converted to azido by activation anddisplacement e.g. under Mitsunobu conditions using hydrazoic acid or bytreatment with diphenylphosphorylazide and base, and the azido group inturn may be reduced to amino by hydrogenation.

An example of a group Q¹ convertible to NR² R⁴ is NR^(2′)R^(4′) orhalogen. Halogen may be displaced by an amine HNR^(2′)R^(4′) by aconventional alkylation.

When Q¹ Q² together form a protected oxo group this may be an acetalsuch as ethylenedioxy which can subsequently be removed by acidtreatment to give a compound of formula (VI):

wherein the variables are as described for formula (I)

The ketone of formula (VI) is reacted with an amine HNR^(2′)R^(4′) byconventional reductive alkylation as described above for process variant(x).

Examples of groups Z^(1′), Z^(2′), Z^(3′), Z^(4′), Z⁵ convertible to Z¹,Z², Z³, Z⁴ and Z⁵ include CR^(1a′) where R^(1a′) is a group convertibleto R^(1a). Z^(1′), Z^(2′), Z^(3′), Z^(4′) and Z^(5′) are preferably Z¹,Z², Z³, Z⁴ and Z⁵.

R^(1a′), R^(1′) and R^(2′) are preferably R^(1a), R¹ and R². R^(1′) ispreferably methoxy. R^(2′) is preferably hydrogen. R^(3′) is R³ or morepreferably hydrogen, vinyl, alkoxycarbonyl or carboxy. R^(4′) is R⁴ ormore preferably H or an N-protecting group such as t-butoxycarbonyl,benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.

Conversions of R^(1′), R^(2′), R^(3′) and R⁴ and interconversions of R¹,R², R³ and R⁴ are conventional. In compounds which contain an optionallyprotected hydroxy group, suitable conventional hydroxy protecting groupswhich may be removed without disrupting the remainder of the moleculeinclude acyl and alkylsilyl groups. N-protecting groups are removed byconventional methods.

For example R^(1′) methoxy is convertible to R^(1′) hydroxy by treatmentwith lithium and diphenylphosphine (general method described in Irelandet al, J. Amer. Chem. Soc., 1973, 7829) or HBr. Alkylation of thehydroxy group with a suitable alkyl derivative bearing a leaving groupsuch as halide and a protected amino, piperidyl, amidino or guanidinogroup or group convertible thereto, yields, afterconversion/deprotection, R¹ alkoxy substituted by optionallyN-substituted amino, piperidyl, guanidino or amidino.

R³ alkenyl is convertible to hydroxyalkyl by hydroboration using asuitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation andreduction or oxymercuration.

R³ 1,2-dihydroxyalkyl can be prepared from R^(3′) alkenyl using osmiumtetroxide or other reagents well known to those skilled in the art (seeAdvanced Organic Chemistry, Ed. March, J, John Wiley and Sons, 1985, p732–737 and refs. cited therein) or epoxidation followed by hydrolysis(see Advanced Organic Chemistry, Ed. March, J John Wiley and Sons, 1985,p 332,333 and refs. cited therein).

R³ vinyl can be chain extended by standard homologation, e.g. byconversion to hydroxyethyl followed by oxidation to the aldehyde, whichis then subjected to a Wittig reaction.

Opening an epoxide-containing R^(3′) group with cyanide anion yields aCH(OH)—CH₂CN group.

Opening an epoxide-containing R^(3′) group with azide anion yields anazide derivative which can be reduced to the amine. Conversion of theamine to a carbamate is followed by ring closure with base to give the2-oxo-oxazolidinyl containing R³ group.

Substituted 2-oxo-oxazolidinyl containing R³ groups may be prepared fromthe corresponding aldehyde by conventional reaction with a glycine anionequivalent, followed by cyclisation of the resulting amino alcohol (M.Grauert et al, Ann. Chem., 1985, 1817; Rozenberg et al, Angew. Chem.Int. Ed. Engl., 1994, 33(1), 91). The resulting 2-oxo-oxazolidinyl groupcontains a carboxy group which can be converted to other R¹⁰ groups bystandard procedures.

Carboxy groups within R³ may be prepared by Jones' oxidation of thecorresponding alcohols CH₂OH using chromium acid and sulphuric acid inwater/methanol (E. R. H. Jones et al, J. Chem. Soc., 1946, 39). Otheroxidising agents may be used for this transformation such as sodiumperiodate catalysed by ruthenium trichloride (G. F. Tutwiler et al, J.Med. Chem., 1987, 30(6), 1094), chromium trioxide-pyridine (G. Just etal, Synth. Commun., 1979, 9(7), 613), potassium permanganate (D. E.Reedich et al, J. Org. Chem., 1985, 50(19), 3535), and pyridiniumchlorochromate (D. Askin et al, Tetrahedion Lett., 1988, 29(3), 277).

The carboxy group may alternatively be formed in a two stage process,with an initial oxidation of the alcohol to the corresponding aldehydeusing for instance dimethyl sulphoxide activated with oxalyl chloride(N. Cohen et al, J. Am. Chem. Soc., 1983, 105, 3661) ordicyclohexylcarbodiimide (R. M. Wengler, Angew. Chim. Int. Ed. Eng.,1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate(Ley et al, J. Chem. Soc. Chem Commun., 1987, 1625). The aldehyde maythen be separately oxidised to the corresponding acid using oxidisingagents such as silver (II) oxide (R. Grigg et al, J. Chem. Soc. Perkin1,1983, 1929), potassium permanganate (A. Zurcher, Helv. Chim. Acta.,1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride(T. Sakata et al, Bull: Chem. Soc. Jpn., 1988, 61(6), 2025), pyridiniumchlorochromate (R. S. Reddy et al, Synth. Commun., 1988, 18(51), 545) orchromium trioxide (R. M. Coates et al, J. Am. Chem. Soc., 1982, 104,2198).

An R³ CO₂H group may also be prepared from oxidative cleavage of thecorresponding diol, CH(OH)CH₂OH, using sodium periodate catalysed byruthenium trichloride with an acetontrile-carbontetrachloride-watersolvent system (V. S. Martin et al, Tetrahedron Letters, 1988, 29(22),2701).

Other routes to the synthesis of carboxy groups within R³ are well knownto those skilled in the art.

R³ groups containing a cyano or carboxy group may also be prepared byconversion of an alcohol to a suitable leaving group such as thecorresponding tosylate by reaction with para-toluenesulphonyl chloride(M. R. Bell, J. Med. Chem., 1970, 13, 389), or the iodide usingtriphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun.,1990, 20, 1473). The second stage is the displacement of the leavinggroup with cyanide anion (L. A. Paquette et al, J. Org. Chem., 1979,44(25), 4603; P. A. Grieco et al, J. Org. Chem., 1988, 53(16), 3658.Finally acidic hydrolysis of the nitrile group gives the desired acids(H. Rosemeyer et al, Heterocycles, 1985, 23 (10), 2669). The hydrolysismay also be carried out with base e.g. potassium hydroxide (H. Rapoport,J. Org. Chem., 1958, 23, 248) or enzymatically (T. Beard et al,Tetrahedron Asymmetry, 1993, 4 (6), 1085).

R³ cis or trans hydroxy may be introduced by the methods of van Deale etal., Drug Development Research 8:225–232 (1986) or Heterocycles 39(1),163–170 (1994). For trans hydroxy, a suitable method convertsN-protected tetrahydropyridine to the epoxide by treatment withmetachloroperbenzoic acid, followed by opening of the epoxide with asuitable amine NR^(2′)R^(4′).

Other functional groups in R³ may be obtained by conventionalconversions of hydroxy, carboxy or cyano groups.

Tetrazoles are conveniently prepared by reaction of sodium azide withthe cyano group (e.g. F. Thomas et al, Bioorg. Med. Chem. Lett., 1996,6(6), 631; K. Kubo et al, J. Med. Chem., 1993, 36, 2182) or by reactionof azidotri-n-butyl stannane with the cyano group followed by acidichydrolysis (P. L. Ornstein, J. Org. Chem., 1994, 59, 7682 and J. Med.Chem, 1996, 39 (11), 2219).

The 3-hydroxy-3-cyclobutene-1,2-dion-4-yl group (e.g. R. M. Soll,Bioorg. Med. Chem. Lett., 1993, 3(4), 757 and W. A. Kinney, J. Med.Chem., 1992, 35(25), 4720) can be prepared by the followingsequence:—(1) a compound where R³ is (CH₂)_(n)CHO (n=0, 1, 2) is treatedwith triethylamine, carbon tetrabromide-triphenylphosphine to giveinitially (CH₂)_(n)CH═CHBr; (2) dehydrobromination of this intermediateto give the corresponding bromoethyne derivative (CH₂)_(n)C≡CBr (forthis 2 stage sequence see D. Grandjean et al, Tetrahedron Lett., 1994,35(21), 3529); (3) palladium-catalysed coupling of the bromoethyne with4-(1-methylethoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione(Liebeskind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of theethyne moiety to —CH₂CH₂— under standard conditions of hydrogen andpalladium on charcoal catalysis (see Howard et al, Tetrahedron, 1980,36, 171); and finally (4) acidic hydrolysis of the methyl ethoxyester togenerate the corresponding 3-hydroxy-3-cyclobutene-1,2-dione group (R.M. Soll, Bioorg. Med. Chem. Lett., 1993, 3(4), 757).

The tetrazol-5-ylaminocarbonyl group may be prepared from thecorresponding carboxylic acid and 2-aminotetrazole by dehydration withstandard peptide coupling agents such as 1,1′-carbonyldiimidazole (P. L.Ornstein et al, J. Med Chem, 1996, 39(11), 2232).

The alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared fromthe corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamideby dehydration with standard peptide coupling agents such as1,1′-carbonyldiimidazole (P. L. Ornstein et al, J. Med. Chem., 1996,39(11), 2232).

The hydroxamic acid groups are prepared from the corresponding acids bystandard amide coupling reactions e.g. N. R. Patel et al, Tetrahedron,1987, 43(22), 5375.

2,4-Thiazolidinedione groups may prepared from the aldehydes bycondensation with 2,4-thiazolidinedione and subsequent removal of theolefinic double bond by hydrogenation.

The preparation of 5-oxo-1,2,4-oxadiazoles from nitrites is decribed byY. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17), 1903.

1,2,4-Triazol-5-yl groups may be prepared from the corresponding nitrileby reaction with an alcohol under acid conditions followed by reactionwith hydrazine and then an R¹⁰-substituted activated carboxylic acid(see J. B. Polya in “Comprehensive Heterocyclic Chemistry” Edition 1,p762, Ed A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984and J. J. Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).

Other substituents on R³ alkyl or alkenyl may be interconverted byconventional methods, for example hydroxy may be derivatised byesterification, acylation or etherification. Hydroxy groups may beconverted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino,aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonylby conversion to a leaving group and substitution by the required groupor oxidation as appropriate or reaction with an activated acid,isocyanate or alkoxyisocyanate. Primary and secondary hydroxy groups canbe oxidised to an aldehyde or ketone respectively and alkylated with asuitable agent such as an organometallic reagent to give a secondary ortertiary alcohol as appropriate. A carboxylate group may be converted toan hydroxymethyl group by reduction of an ester of this acid with asuitable reducing agent such as lithium aluminium hydride.

An NH₂ substituent on piperidine is converted to NR²R⁴ by conventionalmeans such as amide or sulphonamide formation with an acyl derivativeR⁵COW or R⁵SO₂W, for compounds where U is CO or SO₂ or, where U is CH₂,by alkylation with an alkyl halide R⁵CH₂-halide in the presence of base,acylation/reduction with an acyl derivative R⁵COW or reductivealkylation with an aldehyde R⁵CHO.

Where one of R³ and R⁶, R⁷, R⁸ or R⁹ contains a carboxy group and theother contains a hydroxy or amino group they may together form a cyclicester or amide linkage. This linkage may form spontaneously duringcoupling of the compound of formula (IV) and the piperidine moiety or inthe presence of standard peptide coupling agents.

It will be appreciated that under certain circumstances interconvertionsmay interfere, for example, A or B hydroxy groups in A or B and thepiperidine substituent NH₂ will require protection e.g. as a carboxy- orsilyl-ester group for hydroxy and as an acyl derivative for piperidineNH₂, during conversion of R^(1′), R^(2′), R^(3′) or R^(4′), or duringthe coupling of the compounds of formulae (IV) and (V).

Compounds of formulae (IV) and (V) are known compounds, (see for exampleSmith et al, J. Amer. Chem. Soc., 1946, 68, 1301) or preparedanalogously.

Compounds of formula (IV) where X is CR⁶R⁷SO₂W may be prepared by aroute analogous to that of Ahmed El Hadri et al, J. Heterocyclic Chem.,1993, 30(3), 631. Thus compounds of formula (IV) where X is CH₂SO₂OH maybe prepared by reacting the corresponding 4-methyl compound withN-bromosuccinimide, followed by treatment with sodium sulfite. Theleaving group W may be converted to another leaving group W, e.g. ahalogen group, by conventional methods.

The isocyanate of formula (IV) may be prepared conventionally from a4-amino derivative such as 4-amino-quinoline, and phosgene, or phosgeneequivalent (eg triphosgene) or it may be prepared more conveniently froma 4-carboxylic acid by a “one-pot” Curtius Reaction with diphenylphosphoryl azide (DPPA) [see T. Shiori et al. Chem. Pharm. Bull. 35,2698–2704 (1987)].

The 4-amino derivatives are commercially available or may be prepared byconventional procedures from a corresponding 4-chloro or4-trifluoromethanesulphonate derivative by treatment with ammonia (O. G.Backeberg et. al., J. Chem Soc., 381, 1942) or propylamine hydrochloride(R. Radinov et. al., Synthesis, 886, 1986).

4-Alkenyl compounds of formula (IV) may be prepared by conventionalprocedures from a corresponding 4-halogeno-derivative by e.g. a Hecksynthesis as described in e.g. Organic Reactions, 1982, 27, 345.

4-Halogeno derivatives of compounds of formula (IV) are commerciallyavailable, or may be prepared by methods known to those skilled in theart. A 4-chloroquinoline is prepared from the correspondingquinolin-4-one by reaction with phosphorus oxychloride (POCl₃) orphosphorus pentachloride, PCl₅. A 4-chloroquinazoline is prepared fromthe corresponding quinazolin-4-one by reaction with phosphorusoxychloride (POCl₃) or phosphorus pentachloride, PCl₅. A quinazolinoneand quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C.Elderfield.

4-Carboxy derivatives of compounds of formula (IV) are commerciallyavailable or may be prepared by conventional procedures for preparationof carboxy heteroaromatics well known to those skilled in the art. Forexample, quinazolines may be prepared by standard routes as described byT. A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C.Elderfield. These 4-carboxy derivatives may be activated by conventionalmeans, e.g. by conversion to an acyl halide or anhydride.

Pyridazines may be prepared by routes analogous to those described inComprehensive Heterocyclic Chemistry, Volume 3, Ed A. J. Boulton and A.McKillop and napthyridines may be prepared by routes analogous to thosedescribed in Comprehensive Heterocyclic Chemistry, Volume 2, Ed A. J.Boulton and A. McKillop.

A 4-oxirane derivative of compounds of formula (IV) is convenientlyprepared from the 4-carboxylic acid by first conversion to the acidchloride with oxalyl chloride and then reaction withtrimethylsilyldiazomethane to give the diazoketone derivative.Subsequent reaction with 5M hydrochloric acid gives thechloromethylketone. Reduction with sodium borohydride in aqueousmethanol gives the chlorohydrin which undergoes ring closure to affordthe epoxide on treatment with base, e.g. potassium hydroxide inethanol-tetrahydrofuran.

Alternatively and preferably, 4-oxirane derivatives can be prepared frombromomethyl ketones which can be obtained from 4-hydroxy compounds byother routes well known to those skilled in he art. For example, hydroxycompounds can be converted to the corresponding4-trifluoromethanesulphonates by reaction with trifluoromethanesulphonicanhydride under standard conditions (see K. Ritter, Synthesis, 1993,735). Conversion into the corresponding butyloxyvinyl ethers can beachieved by a Heck reaction with butyl vinyl ether under palladiumcatalysis according to the procedure of W. Cabri et al, J. Org. Chem,1992, 57 (5), 1481. (Alternatively, the same intermediates can beattained by Stille coupling of the trifluoromethanesulphonates or theanalaogous chloro derivatives with (1-ethoxyvinyl)tributyl tin, T. R.Kelly, J. Org. Chem., 1996, 61, 4623.) The alkyloxyvinyl ethers are thenconverted into the corresponding bromomethylketones by treatment withN-bromosuccinimide in aqueous tetrahydrofuran in a similar manner to theprocedures of J. F. W. Keana, J. Org. Chem., 1983, 48, 3621 and T. R.Kelly, J. Org. Chem., 1996, 61, 4623.

The 4-hydroxyderivatives can be prepared from an aminoaromatic byreaction with methylpropiolate and subsequent cyclisation, analogous tothe method described in N. E. Heindel et al, J. Het. Chem., 1969, 6, 77.For example, 5-amino-2-methoxy pyridine can be converted to4-hydroxy-6-methoxy-[1,5]naphthyridine using this method.

If a chiral reducing agent such as (+) or(−)-B-chlorodiisopinocamphenylborane [‘DIP-chloride’] is substituted forsodium borohydride, the prochiral chloromethylketone is converted intothe chiral chlorohydrin with ee values generally 85–95% [see C. Bolm etal, Chem. Ber. 125, 1169–1190, (1992)]. Recrystallisation of the chiralepoxide gives material in the mother liquor with enhanced optical purity(typically ee 95%).

The (R)-epoxide, when reacted with a piperidine derivative givesethanolamine compounds as single diastereomers with (R)-stereochemistryat the benzylic position.

Alternatively, the epoxide may be prepared from the 4-carboxaldehyde bya Wittig approach using trimethylsulfonium iodide [see G. A. Epling andK-Y Lin, J. Het. Chem., 1987, 24, 853–857], or by epoxidation of a4-vinyl derivative.

4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridinederivatives by reaction with diethyl ethoxymethylene malonate to producethe 4-hydroxy-3-carboxylic acid ester derivative with subsequenthydrolysis to the acid, followed by thermal decarboxylation in quinoline(as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylicacid, J. T. Adams et al., J. Amer. Chem. Soc., 1946, 68, 1317). A4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivativeby heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or4-trifluoromethanesulphonyloxy derivative by reaction withmethanesulphonyl chloride or trifluoromethanesulphonic anhydride,respectively, in the presence of an organic base. A 4-amino1,5-naphthyridine can be obtained from the 4-chloro derivative byreaction with n-propylamine in pyridine.

Similarly, 6-methoxy-1,5-naphthyridine derivatives can be prepared from3-amino-6-methoxypyridine.

1,5-Naphthyridines may be prepared by other methods well known to thoseskilled in the art (for examples see P. A. Lowe in “ComprehensiveHeterocyclic Chemistry” Volume 2, p581–627, Ed A. R. Katritzky and C. W.Rees, Pergamon Press, Oxford, 1984).

The 4-hydroxy and 4-amino-cinnolines may be prepared following methodswell known to those skilled in the art [see A. R. Osborn and K.Schofield, J. Chem. Soc. 2100 (1955)]. For example, a2-aminoacetopheneone is diazotised with sodium nitrite and acid toproduce the 4-hydroxycinnoline with conversion to chloro and aminoderivatives as described for 1,5-naphthyridines.

For compounds of formula (V), suitable amines may be prepared from thecorresponding 4-substituted piperidine acid or alcohol. In a firstinstance, an N-protected piperidine containing an acid bearingsubstituent, can undergo a Curtius rearrangement and the intermediateisocyanate can be converted to a carbamate by reaction with an alcohol.Conversion to the amine may be achieved by standard methods well knownto those skilled in the art used for amine protecting group removal. Forexample, an acid substituted N-protected piperidine can undergo aCurtius rearrangement e.g. on treatment with diphenylphosphoryl azideand heating, and the intermediate isocyanate reacts in the presence of2-trimethylsilylethanol to give the trimethylsilylethylcarbamate (T. L.Capson & C. D. Poulter, Tetrahedron Lett., 1984, 25, 3515). Thisundergoes cleavage on treatment with tetrabutylammonium fluoride to givethe 4-amine substituted N-protected piperidine.

In a second instance, an N-protected piperidine containing an alcoholbearing substituent undergoes a Mitsunobu reaction (for example asreviewed in Mitsunobu, Synthesis, (1981), 1), for example withsuccinimide in the presence of diethyl azodicarboxylate andtriphenylphosphine to give the phthalimidoethylpiperidine. Removal ofthe phthaloyl group, for example by treatment with methylhydrazine,gives the amine of formula (V).

R⁵CH₂-halides, acyl derivative R⁵COW and R⁵SO₂W or aldehydes R⁵CHO arecommercially available or are prepared conventionally. The aldehydes maybe prepared by partial reduction of the R⁵-ester with lithium aluminiumhydride or di-isobutylaluminium hydride or more preferably by reductionto the alcohol, with lithium aluminium hydride or sodium borohydride orlithium triethylborohydride (see Reductions by the Alumino- andBorohydrides in Organic Synthesis, 2nd ed., Wiley, N.Y., 1997; JOC,3197, 1984; Org. Synth. Coll., 102, 1990; 136, 1998; JOC, 4260, 1990;TL, 995, 1988; JOC, 1721, 1999; Liebigs Ann./Recl., 2385, 1997; JOC,5486, 1987), followed by oxidation to the aldehyde with manganese (II)dioxide. The aldehydes may also be prepared from carboxylic acids in twostages by conversion to a mixed carbonate for example by reaction withisobutyl chloroformate followed by reduction with sodium borohydride (R.J. Alabaster et al., Synthesis, 598, 1989) to give the hydroxymethylsubstituted heteroaromatic or aromatic and then oxidation with astandard oxidising agent such as pyridinium dichromate or manganese (II)dioxide. Acyl derivative R⁵COW may be prepared by activation of theR⁵-ester. R⁵CH₂-halides such as bromides may be prepared from thealcohol R⁵CH₂OH by reaction with phosphorus tribromide inDCM/triethylamine.

Alternatively the aldehyde R⁵CHO and sulphonic acid derivative R⁵SO₂Wmay be generated by treatment of the R⁵H heterocycle with suitablereagents. For example benzoxazinones, or more preferably theirN-methylated derivatives can be formylated with hexamine in eithertrifluoroacetic acid or methanesulfonic acid, in a modified Duffprocedure [O. I. Petrov et al. Collect. Czech. Chem. Commun. 62, 494–497(1997)]. 4-Methyl-4H-benzo[1,4]oxazin-3-one may also be formylated usingdichloromethyl methyl ether and aluminium chloride giving exclusivelythe 6-formyl derivative. Reaction of a R⁵H heterocycle withchlorosulphonic acid gives the sulphonic acid derivative (by methodsanalogous to Techer et. al., C. R. Hebd. Seances Acad. Sci. Ser. C; 270,1601, 1970).

The aldehyde R⁵CHO may be generated by conversion of an R⁵halogen orR⁵trifluoromethane sulphonyloxy derivative into an olefin withsubsequent oxidative cleavage by standard methods. For example, reactionof a bromo derivative under palladium catalysis withtrans-2-phenylboronic acid under palladium catalysis affords a styrenederivative which upon ozonolysis affords the required R⁵CHO (Stephenson,G. R., Adv. Asymmetric Synth. (1996), 275–298. Publisher: Chapman &Hall, London).

R⁵ heterocycles are commercially available or may be prepared byconventional methods. For example where a benzoxazinone is required, anitrophenol may be alkylated with for example ethyl bromoacetate and theresulting nitro ester reduced with Fe in acetic acid (alternativelyZn/AcOH/HCl or H₂ Pd/C or H₂ Raney Ni). The resulting amine will undergospontaneous cyclisation to the required benzoxazinone. Alternatively anitrophenol may be reduced to the aminophenol, which is reacted withchloroacetyl chloride [method of X. Huang and C. Chan, Synthesis 851(1994)] or ethyl bromoacetate in DMSO [method of Z. Moussavi et al. Eur.J. Med. Chim. Ther. 24, 55–60 (1989)]. The same general routes can beapplied to prepare benzothiazinones [See for example F. Eiden and F.Meinel, Arch. Pharm. 312, 302–312 (1979), H. Fenner and R GrauertLiebigs. Ann. Chem. 193–313 (1978)]]. A variety of routes are availableto prepare aza analogues of benzothiazinones via the key correspondingaldehydes. For instance,2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carbaldehyde may beaccessed from 5-fluoro-2-picoline (E. J. Blanz, F. A. French, J. R.DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124–1130) byconstructing the thiazinone ring onto the pyridyl ring thenfunctionalising the methyl substituent, as described in the Examples.The dioxin analogue of this aza substitution patern,2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde is accessiblefrom Kojic acid by aminolysis from pyrone to pyridone then annelatingthe dioxin ring, again as described in the subsequent experimental data.Other aza substitution patterns with pyridothiazin-3-one,pyridooxazin-3-one, and pyridodioxin ring systems are also accessible,again as descibed in the Examples. Ortho-aminothidphenols may beconveniently prepared and reacted as their zinc complexes [see forexample V. Taneja et al Chem. Ind. 187 (1984)]. Benzoxazolones may beprepared from the corresponding aminophenol by reaction with carbonyldiimidazole, phosgene ot triphosgene. Reaction of benzoxazolones withdiphosporus pentasulfide affords the corresponding 2-thione. Thiazinesand oxazines can be prepared by reduction of the correspondingthiazinone or oxazinone with a reducing agent such as lithium aluminiumhydride.

The amines R^(2′)R^(4′)NH are available commercially or preparedconventionally. For example amines R⁵CH₂NH₂ may be prepared from abromomethyl derivative by reaction with sodium azide indimethylformamide (DMF), followed by hydrogenation of the azidomethylderivative over palladium-carbon. An alternative method is to usepotassium phthalimide/DMF to give the phthalimidomethyl derivative,followed by reaction with hydrazine in DCM to liberate the primaryamine.

Conversions of R^(1a′), R^(1′), R^(2′), R^(3′) and R^(4′) may be carriedout on the intermediates of formulae (IV), and (V) prior to theirreaction to produce compounds of formula (I) in the same way asdescribed above for conversions after their reaction.

Further details for the preparation of compounds of formula (I) arefound in the examples.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by a combinatorial “split andmix” approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I) orpharmaceutically acceptable derivatives thereof.

Novel intermediates of formulae (IV) and (V) are also part of thisinvention.

The antibacterial compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibacterials.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The composition may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10–60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50–500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable derivative thereof is administered in theabove-mentioned dosage range.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with otherantibacterials. If the other antibacterial is a β-lactam then aβ-lactamase inhibitor may also be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms.

Abbreviations in the examples:

-   RT=room temperature-   ES=Electrospray mass spec.-   LCMS=Liquid chromatography mass spec.-   APCI+=Atmospheric pressure chemical ionisation mass spec

EXAMPLES Example 1(R)-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanoldioxalate

(a) 6-Methoxyquinoline-4-carboxylic acid

The title compound was prepared by modification of the proceduredescribed by W. E. Doering and J. D. Chanley, J. Amer. Chem. Soc., 1946,68, 586. A mixture of quinone (derived from quinine by reaction withpotassium tert-butoxide and benzophenone in toluene) (225 g, 0.70 mol),tert-butanol (1 liter) and water (10 ml) was treated with potassiumt-butoxide (170 g, 1.5 mol). The mixture was stirred at 30° C., whileair was bubbled through for 3 days. The mixture was diluted with diethylether and water and the layers separated. The aqueous phase wasextracted with ethyl acetate. The combined diethyl ether and ethylacetate extracts were dried over magnesium sulfate and evaporated togive recovered starting material (approximately 100 g). The aqueousphase was acidified to pH5 with 5M hydrochloric acid. The precipitatewas collected by filtration, washed with water and methanol, then driedto give 6-methoxyquinoline-4-carboxylic acid as a yellow solid (64.6 g,46%).

δH (d-6 DMSO) 1.94–1.52 (2H, m), 2.38–2.15 (3H, m), 2.70 (1H, m),3.37–2.92 (5H, m), 5.34–5.06 (2H, m), 6.23–5.95 (1H, m)

(b) [R]-2-(6-Methoxyquinolin-4-yl)oxirane

A solution of 6-methoxyquinoline-4-carboxylic acid (10 g) indichloromethane was heated under reflux with oxalyl chloride (5 ml) anddimethylformamide (2 drops) for 1 hour and evaporated to dryness. Theresidue, in dichloromethane (100 ml) was treated with a 2M solution oftrimethylsilyldiazomethane in hexane (50 ml) and stirred at roomtemperature for 18 hours. 5M Hydrochloric acid (150 ml) was added andthe solution was stirred at room temperature for 3 hours. It wasbasified with sodium carbonate solution, extracted with ethyl acetateand chromatographed on silica gel eluting with ethyl acetate-hexane togive the chloromethyl ketone (4.2 g). A batch of the chloromethyl ketone(20 g) was reduced with (+)-B-chlorodiisopinocamphenylborane (40 g) indichloromethane (400 ml) at room temperature for 18 hours followed bytreatment with diethanolamine (30 g) for 3 hours. The product waschromatographed on silica gel eluting with ethyl acetate-hexane to givethe chloroalcohol (16.8 g), which was dissolved in tetrahydrofuran (100ml) and reacted with sodium hydroxide (2.6 g) in water (13 ml) for 1.5hours. The reaction mixture was evaporated to dryness andchromatographed on silica gel eluting with ethyl acetate—hexane to givethe title compound as a solid (10.4 g) (84% ee by chiral HPLC).

Recrystallisation from ether-pentane gave mother-liquor (7.0 g) (90%ee).

MS (+ve ion electrospray) m/z 202 (N+)

The absolute stereochemistry was defined to be (R) by an NMR study onthe Mosher's esters derived from the product obtained by reaction with1-t-butylpiperazine.

(c)4-tert-Butoxycarbonylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine.

To a stirred solution of [R]-2-(6-methoxyquinolin-4-yl)oxirane (Example1b) (8.07 g, 40.3 mmol) and lithium perchlorate (4.44 g, 40.3 mmol) inanhydrous N,N-dimethylformamide (100 mL) was added4-tert-butoxycarbonylaminopiperidine hydrochloride (11.0 g, 45.7 mmol)and potassium carbonate (6.72, 48.4 mmol). The mixture was heated at 90°C. for 26 hours, then cooled, filtered and evaporated. The residue wasdissolved in ethyl acetate, washed with water, dried and evaporated. Thecrude product was chromatographed on silica gel eluted with 2–5%methanol/dichloromethane to give a gum (11.11 g).

MS (+ve ion electrospray) m/z 402 (MH+).

(d) (R)-2-(4-Amino-piperidin-1-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol

The tert-butoxycarbonylamino compound (1c) (11.11 g, 27.7 mmol) wasdissolved in dichloromethane (30 mL), cooled in ice and treated withtrifluoroacetic acid (30 mL). The solution was stirred at roomtemperature for 1.5 hours, then evaporated in vacuo. After addition oftoluene (50 mL) and re-evaporation, the residue was treated with a 4Msolution of hydrogen chloride in 1,4-dioxan (30 mL). The resulting solidwas triturated, filtered off and washed with ether. This was thenrecrystallised by dissolving in hot methanol, concentrating the solutionand diluting with dichloromethane, to give the trihydrochloride salt(9.4 g). This was dissolved in water, basified to pH9 and evaporated todryness. The residue was extracted several times with 10%methanol/dichloromethane (total 600 mL). The extracts were filtered andevaporated to give the free base as a semi-solid foam (6.45 g).

MS (+ve ion electrospray) m/z 302 (MH+)

(e) Title Compound

A solution of (1d) (100 mg; 0.33 mmol) in dichloromethane (3 ml) andmethanol (1 ml) was treated with activated 3A molecular sieves (1 g) and2,3-dihydrobenzo[1,4]dioxine-6-carboxaldehyde (54 mg, 0.33 mmol). Theresulting solution was stirred at room temperature for 5 hours and thensodium borohydride (25 mg, 0.66 mmol) was added. The resulting slurrywas stirred at room temperature for a further 10 hours. The reactionmixture was quenched by the addition of water (2 ml) and the volatilesremoved in vacuo. The residue was partitioned between ethyl acetate(2×100 ml) and brine (20 ml). The organic phases were combined and driedover magnesium sulphate. The volatiles were again removed under reducedpressure and the resulting oil was subjected to purification on silicagel using a methanol and dichloromethane gradient affording the freebase of the title compound as a colourless oil (35 mg, 23%)

δH (CDCl₃): 1.40–2.65 (8H, m), 2.79–2.68 (2H, m), 3.20–3.35 (1H, m),3.72 (2H, s), 3.93 (3H, s), 4.25 (4H, s), 5.30–5.45 (1H, dd), 6.76–6.85(3H, m), 7.18 (1H, d), 7.34–7.39 (1H, dd), 7.64 (1H, d), 8.03 (1H, d),8.76 (1H, d).

MS (+ve ion electrospray) m/z 450 (MH+).

A solution of the oil (35 mg) in dichloromethane (1 ml) was added tooxalic acid (14 mg) in diethyl ether (10 ml) to generate the dioxalatesalt. The title compound was isolated by centrifugation, washing withdiethyl ether and subsequent drying in vacuo.

Example 2(R)-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanoldioxalate

(a) 6-Methoxy-1H-[1,5]naphthyridin-4-one

5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 ml) withmethyl propiolate (40 ml, 0.44 mol) was stirred for 48 hours, thenevaporated and the product purified by chromatography on silica gel(dichloromethane) followed by recrystallisation fromdichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5 g,0.05 mol) in warm Dowtherm A (50 ml) was added over 3 minutes torefluxing Dowtherm A, and after a further 20 minutes at reflux themixture was cooled and poured into ether. The precipate was filtered togive a white solid (6.26 g, 70%).

(b) 1,1,1-Trifluoro-methanesulfonic acid6-methoxy-[1,5]naphthyridin-4-yl ester

The naphthyridine (2a) (10 g, 0.057 mol) in dichloromethane (200 ml)containing 2,6-lutidine (9.94 ml, 0.086 mol) and 4-dimethylaminopyridine(0.07 g, 0.0057 mol) was cooled in ice and treated withtrifluoromethanesulfonic anhydride (10.5 ml, 0.063 mol). After stirringfor 2.5 hours the mixture was washed with saturated ammonium chloridesolution, dried, evaporated and purified on silica (dichloromethane).

(c) Bromomethyl-(6-methoxy-[1,5]-naphthyridin-4-yl)-ketone

The triflate (2b) (13.2 g, 0.044 mol) in N,N-dimethylformamide (200 ml)with triethylamine (12 ml, 0.086 mol), butyl vinyl ether (22 ml, 0.17mol), palladium (II) acetate (0.97 g, 0.0044 mol) and1,3-bis(diphenylphosphino)propane (1.77 g, 0.0044 mol) was heated at 60°C. for 3 hours then evaporated and chromatographed on silica gel(dichloromethane) to give a yellow solid (10.7 g, 95%). This wasdissolved in tetrahydrofuran (250 ml) and water (40 ml) then treatedwith N-bromosuccinimide (7.4 g, 0.042 mol) for 1 hour. Evaporation andchromatography on silica gel (dichloromethane) gave the ketone (10.42 g,98%).

(d) (R)-2-Bromo-1-(6-methoxy-[1,5]-naphthyridin-4-yl)ethanol

The bromomethyl ketone (2c) (6.6 g, 0.023 mol) in toluene was treatedwith (+)-B-chlorodiisopinocamphenylborane ((+)-DIP-chloride) (12 g,0.037 mol) and stirred overnight, then diethanolamine (15 g, 0.14 mol)added and the mixture stirred for 3 hours, filtered and evaporated.Chromatography on silica gel (ethyl acetate-hexane) gave a white solid(4.73 g, 73%).

(e) (R)-2-(6-Methoxy-[1,5]-naphthyridin-4-yl)oxirane

The alcohol (2d) (4.8 g, 0.017 mol) in methanol (20 ml) was stirred withpotassium carbonate (2.6 g, 0.019 mol) for 1 hour, then evaporated andchromatographed on silica gel (ethyl acetate-hexane-dichloromethane) togive a solid (3.14 g, 92%), (91% ee by chiral HPLC).

MS (+ve ion electrospray) m/z 203 (MH+).

(f)(R)-2-(4-Amino-piperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol

This was prepared in similar overall yield from oxirane (2e) by themethod of Example (1c,d).

MS (+ve ion electrospray) m/z 303 (MH+).

(g) Title Compound

This was prepared from amine (2f) and2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde by the same reductivealkylation procedure as for Example 1, giving the free base of the titlecompound as an oil (223 mg, 49%).

δH (CDCl₃): 1.60 (2H, m), 2.05 (2H, m), 2.25 (1H, m), 2.45 (2H, m), 2.70(1H, m), 2.85 (1H, m), 3.10 (1H, m), 3.30 (1H, m), 3.75 (2H, s), 4.00(3H, s), 4.25 (4H, s), 5.75 (1H, dd), 6.80–6.90 (3H, m), 7.10 (1H, d),7.80 (1H, d), 8.22 (1H, d), 8.78 (1H, d).

MS (+ve ion electrospray) m/z 451 (MH+)

The dioxalate salt was prepared by the same method as for Example 1.

Example 3(R)-2-{4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanoldioxalate

The title compound was prepared in the same manner as Example 1 usingbenzo[1,3]dioxole-5-carboxaldehyde as the aldehyde component. The crudereaction mixture was purified by chromatography on silica gel using amethanol and dichloromethane gradient to afford the free base of thetitle product as a colourless oil (48 mg, 33%).

δH (CDCl₃): 1.40–2.65 (8H, m), 2.80–2.85 (2H, m), 3.21 (1H, m), 3.74(2H, s), 3.93 (3H, s), 5.40–5.44 (1H, dd), 5.94 (2H, s), 6.77 (2H, m),6.84 (1H, s), 7.18 (1H, d), 7.34–7.39 (1H, dd), 7.64 (1H, d), 8.04 (1H,d), 8.76 (1H, d).

MS (+ve ion electrospray) m/z 436 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 4(R)-2-{4-[(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanoldioxolate

The title compound was prepared in the same manner as Example 1 usingdifluoro-benzo[1,3]dioxole-5-carboxaldehyde as the aldehyde component.The crude reaction mixture was purified by chromatography on silica gelusing a methanol and dichloromethane gradient to afford the the freebase of the title product as a colourless oil (30 mg, 19%).

δH (CDCl₃): 1.40–2.65 (8H, m), 2.80–2.85 (2H, m), 3.24–3.28 (1H, m),3.82 (2H, s), 3.93 (3H, s), 5.46–5.41 (1H, dd), 6.97–7.05 (2H, m), 7.11(1H, d), 7.18 (1H, d), 7.34–7.39 (1H, dd), 7.64 (1H, d), 8.04 (1H, d),8.77 (1H, d).

MS (+ve ion electrospray) m/z 472 (NH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 56-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-onedioxalate

(a) (4-Formyl-2-nitro-phenoxy)-acetic acid ethyl ester

A solution of 4-hydroxy-3-nitro-benzaldehyde (6.9 g) and ethylbromoacetate (5.0 ml) in dimethylformamide (250 ml) was treated withanhydrous potassium carbonate (10 g) and the mixture was heated at 60°C. for 18 hours and evaporated to dryness. The residue was partitionedbetween water and ether, and the ether layer was washed with 0.5M sodiumhydroxide, dried over anhydrous sodium sulphate and evaporated to givean oil that was chromatographed on silica gel (ethylacetate/dichloromethane) to afford an oil (1.9 g)

MS (+ve ion electrospray) m/z 253 (MH+).

(b) 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde

The ester (5a) (1.9 g) in acetic acid (40 ml) was treated with ironpowder (4.2 g) and the mixture was stirred at 60° C. for 0.75 hours,filtered and evaporated to dryness. It was partitioned between aqueoussodium bicarbonate and ethyl acetate. The organic fraction waschromatographed on silica gel (ethyl acetate) to give a white solid(0.88 g).

MS (−ve ion electrospray) m/z 176 (M−H)⁻

(c) Title Compound

A solution of theamine (1d) (300 mg) and carboxaldehyde (5b) (177 mg) inchloroform (3 ml) and methanol (0.5 ml) was treated with 3A molecularsieves and the mixture was heated under reflux for 3.5 hours. The cooledsolution was treated with sodium borohydride (76 mg) in methanol (3 ml)and after 0.5 hours water was added and the mixture was extracted withchloroform, dried over sodium sulfate, and evaporated. It waschromatographed on silica gel (10% ammonia in methanol/ethyl acetate) toafford the free base of the title compound as a foam (0.24 g).

δH (CDCl₃): 1.55 (2H, m), 1.90–2.60 (8H, m), 2.85 (2H, m), 3.30 (1H, m),3.50 (2H, s), 3.72 (2H, s), 3.90 (3H, s), 5.43 (1H, dd), 6.82 (1H, s),6.92 (2H, s), 7.15 (1H, d), 7.35 (1H, dd), 7.65 (1H, d), 8.05 (1H, d),8.80 (1H, d)

MS (+ve ion electrospray) m/z 463 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 66-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-onedioxalate

(a) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester(6.74 g) was suspended in tetrahydrofuran (100 ml) and 2M sodiumhydroxide (30 ml) was added followed by water (20 ml). The solution wasstirred for 2.5 hours, evaporated to half volume and acidified with 2Mhydrochloric acid. The product was collected, washed with water anddried in vacuo, to give a white solid (6.2 g).

MS (−ve ion electrospray) m/z 208 (M−H)⁻

(b) 6-Hydroxymethyl-4H-benzo[1,4]thiazin-3-one

The acid (6a) in tetrahydrofuran (50 ml) and triethylamine (4.7 ml) wascooled to 0° C. and isobutylchloroformate (4.02 ml) was added dropwiseand the solution was stirred at 0° C. for 2 hours, when it was filteredinto a stirred solution of sodium borohydride (3.14 g) in ice/water (50ml). The mixture was stirred at 0° C. for 1 hour and allowed to warm toroom temperature. It was acidified with 2M hydrochloric acid, evaporatedto half volume, and the resulting product was collected, washed withwater and dried in vacuo, to give a white solid (4.5 g).

MS (−ve ion electrospray) m/z 194 (M−H)⁻

(c) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde

A stirred solution of the alcohol (6b) (3.5 g) in chloroform (150 ml)and tetrahydrofuran (300 ml) was treated with manganese dioxide (7.8 g)for 18 hours and was filtered and evaporated to give a white solid (2.5g).

MS (−ve ion electrospray) m/z 194 (M−H)⁻

(d) Title Compound

A solution of the amine (1d; 94% ee) (0.40 g) and carboxaldehyde (6c)(0.251 g) in dichloromethane (10 ml) and methanol (10 ml) was treatedwith 3A molecular sieves and the mixture was stirred at room temperaturefor 18 hours. The solution was treated with sodium borohydride (148 mg)in portions and after 3 hours the solution was filtered and evaporatedto dryness. The product in water and chloroform was acidified with 2Mhydrochloric acid, then basified with sodium bicarbonate, extracted withchloroform, dried over sodium sulfate, and evaporated. It waschromatographed on silica gel (methanol/dichloromethane) to afford thefree base of the title compound as a foam (0.34 g).

δH (CDCl₃): 1.45 (2H, m), 1.80–2.60 (8H, m), 2.75 (2H, m), 3.20 (1H, m),3.35 (2H, s), 3.75 (2H, s), 3.85 (3H, s), 5.37 (1H, dd), 6.80 (1H, s),6.90 (1H, dd), 7.10 (1H, d) 7.20 (2H, m), 7.30 (1H, dd), 7.55 (1H, d),7.98 (1H, d), 8.40 (1H, brs), 8.70 (1H, d)

MS (+ve ion electrospray) m/z 479 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 74-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-piperidine-1-carboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

(a) 4-Amino-6-methoxy-[1,5]naphthyridine

A solution of the triflate (2b) (8.0 g) and propylamine hydrochloride(15.8 g) in pyridine (120 ml) was heated at reflux for 4 hours. Thesolvent was evaporated and the mixture dissolved in 0.05M hydrochloricacid (600 ml) and washed with dichloromethane. The mixture was basifiedwith 40% aqueous sodium hydroxide and extracted with dichloromethane.The extracts were dried, evaporated and chromatographed on silica gel(2–5% methanol in dichloromethane) to give an orange solid (3.6 g, 63%).

δH (CDCl₃): 4.05 (3H, s), 5.25 (2H, brs), 6.71 (1H, d), 7.08 (1H, d),8.09 (1H, d), 8.39 (1H, d).

MS (+ve ion electrospray) m/z: 176 (MH+).

(b)4-tert-Butyloxycarbonylamino-1-(6-methoxy-[1,5]naphthyridin-4-yl)aminocarbonylpiperidine

To a solution of 4-amino-6-methoxy-[1,5]naphthyridine (7a) (2.1 g, 13.5mmol) and 4-(dimethylamino)pyridine (1.62 g) in anhydrous chloroform (45ml) was added N,N-carbonyldiimidazole (3.28 g, 20.1 mmol). The mixturewas stirred for 4 hours at room temperature, then evaporated and theresidue was dissolved in anhydrous N,N-dimethylformamide (45 ml).4-tert-Butoxycarbonylaminopiperidine hydrochloride (3.34 g, 13.5 mmol)and potassium carbonate (1.89 g) were added, and the mixture was heatedat 70° C. overnight. The mixture was evaporated and the residue wasmixed with water (120 ml). The solid was filtered off and dried (3.89g).

MS (+ve ion electrospray) m/z 402 (MH+).

(c) 4-Amino-1-(6-methoxy-[1,5]naphthyridin-4-yl)aminocarbonylpiperidine

The tert-butoxycarbonylamino compound (7b) (3.88 g, 9.7 mmol) wastreated with trifluoroacetic acid and hydrogen chloride (4M in dioxan)as described in Example (1d). The crude hydrochloride was dissolved inwater and washed twice with dichloromethane, basified to pH 9 andevaporated to dryness. Extraction with 10% methanol/dichloromethane gavethe free base (3.45 g).

MS (+ve ion electrospray) m/z 302 (MH+).

(d) Title Compound

A mixture of amine (7c) (0.15 g), carboxaldehyde (6c) (0.10 g) and 3Amolecular sieves in dichloromethane (3 ml) and methanol (1 ml) wasstirred at room temperature for 18 hours. Sodium borohydride (0.049 g)was added and the mixture was stirred for a further 24 hours. It wasquenched with water and extracted with ethyl acetate. The organic layerwas dried, evaporated and chromatographed on silica gel(methanol/dichloromethane) to afford the free base of the title compoundas a solid (83 mg).

δH (CDCl₃): 1.55 (2H, m), 2.0 (2H, m), 2.80 (1H, m), 3.15 (2H, m), 3.40(2H, s), 3.80 (2H, s), 4.02 (3H, s), 4.10 (2H, m), 6.82 (1H, s), 7.00(1H, d), 7.15 (1H, d) 7.30 (1H, m), 8.10 (1H, br s), 8.20 (1H, d), 8.30(1H, d), 8.65 (1H, d), 9.10 (1H, br s)

MS (+ve ion electrospray) m/z 479 (MH+)

The oxalate salt was prepared by a similar method as for Example 1.

Example 87-Fluoro-6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-onedioxalate

(a) 5-Amino-2-fluoro-4-hydroxy-benzonitrile

This was prepared by from 2-fluoro-4-hydroxy-benzonitrile by nitration(concentrated nitric acid in acetic acid at 40° C.) followed byhydrogenation in ethanol over 10% palladium/carbon.

(b) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile

This was prepared by the general method of Xian Huang and Cheng-ChuChan, Synthesis, 851 (1984). A mixture of amine (8a) (1 g),benzyltriethylammonium chloride (1.5 g) and sodium bicarbonate (2.22 g)in chloroform (20 ml) at 0° C. was treated with chloroacetyl chloride(0.632 ml) in chloroform (5 ml) and then stirred at 5° C. for 1 hour andthen heated at 55° C. for 5 hours. The mixture was evaporated todryness, treated with water, and filtered to give a solid that wasrecrystallised from ethanol to give a white solid (0.35 g). A further(0.24 g) was obtained after chromatography of the mother liquors onsilica gel (chloroform then methanol/dichloromethane).

MS (−ve ion electrospray) m/z 191 (M−H)⁻

(c) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic Acid

The carbonitrile (8b) (0.2 g) was heated under reflux in tetrahydrofuran(20 ml) and water (20 ml) containing sodium hydroxide (0.167 g) for 72hours. It was acidified with 2M hydrochloric acid and the product wascollected and dried in vacuo to give a white solid (0.18 g).

MS (−ve ion electrospray) m/z 210 (M—H)⁻

(d) 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one

This was prepared from carboxylic acid (8c) (1.7 g) by the proceduredescribed in Example (6b) to give a solid (0.7 g).

MS (−ve ion electrospray) m/z 196 (M−H)⁻

(e) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde

This was prepared from the alcohol (8d) (0.7 g) by the proceduredescribed in Example (6c) to give a solid (0.51 g).

MS (−ve ion electrospray) m/z 194 (M−H)⁻

(f) Title Compound

This was prepared from the carboxaldehyde (8e) (117 mg) and amine (1d)(0.15 g) by the procedure described in Example (6d) to give the freebase of the title compound as a foam (0.126 g).

δH (CDCl₃): 1.55 (2H, m), 1.90–2.60 (8H, m), 2.85 (2H, m), 3.30 (1H, m),3.78 (2H, s), 3.90 (3H, s), 4.60 (2H, s), 5.40 (1H, dd), 6.70 (1H, d),6.80 (1H, d), 7.20 (1H, d), 7.35 (1H, dd), 7.65 (1H, d), 8.05 (1H, d),8.80 (1H, d)

MS (+ve ion electrospray) m/z 481 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 96-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-one dioxalate

This was prepared from amine (2f) and aldehyde (5b) by the samereductive alkylation procedure as for Example 5, giving the free base ofthe title compound as an oil (165 mg, 55%).

δH (CDCl₃): 1.60 (2H, m), 2.05 (2H, m), 2.25 (1H, m), 2.45 (2H, m), 2.70(1H, m), 2.85 (2H, m), 3.30 (1H, m), 3.75 (2H, s), 4.00 (3H, s), 4.58(2H, s), 5.75 (1H, dd), 6.90 (3H, m), 7.13 (1H, d), 7.80 (1H, d), 8.25(1H, d), 8.78 (1H, d).

MS (+ve ion electrospray) m/z 464 (MH+)

This material was converted to the dioxalate salt by the procedure ofExample 1.

Example 10(R)-2-{4-[(6-Chloro-benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanoldioxalate

The title compound was prepared in the same manner as Example 1 using6-chloro-benzo[1,3]dioxole-5-carboxaldehyde as the aldehyde component.The crude reaction mixture was purified by chromatography on silica gelusing a methanol and dichloromethane gradient to afford the free base ofthe desired product as a colourless oil (48 mg, 31%).

δH (CDCl₃): 1.25–2.57 (8H, m), 2.79–2.85 (2H, m), 3.22–3.27 (1H, m),3.81 (2H, s), 3.92 (3H, s), 5.40–5.45 (1H, dd), 5.96 (2H, s), 6.83 (1H,s), 6.89 (1H, s), 7.18 (1H, d), 7.34–7.39 (1H, dd), 7.64 (1H, d), 8.03(1H, d), 8.75 (1H, d).

MS (+ve ion electrospray) m/z 470 (MH+).

This material was converted to the dioxalate salt (133 mg) by theprocedure of Example 1.

Example 115-Fluoro-6-({1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-3-methyl-3H-benzoxazol-2-onedioxalate

(a) 5-Fluoro-3H-benzoxazol-2-one

Carbonyl diimidazole (7.6 g) was added to a solution of2-amino-4-fluorophenol (5 g, 39 mmol) in dichloromethane (0.100 ml).After 14 hours the solution was washed with 5M aqueous HCl, water, anddried over magnesium sulfate. The solution was filtered through a plugof silica and evaporated affording a white solid (4.0 g, 66%).

MS (+ve ion electrospray) m/z 154 (MH+)

(b) 5-Fluoro-3-methyl-3H-benzoxazol-2-one

A solution of (11a) (1.0 g, 6.5 mmol) in tetrahydrofuran/water (10 ml/10ml) was treated with potassium hydroxide (0.51 g, 9.1 mmol) anddimethylsulphate (0.7 ml, 7.2 mmol) then heated at 60° C. for 4 hours.The mixture was evaporated and partitioned between dichloromethane andwater. The dichloromethane extract was dried and evaporated and theresidue chromatographed on silica eluting with an ethylacetate/dichloromethane gradient affording a white solid (0.91 g, 83%).

MS (+ve ion electrospray) m/z 168 (MH+)

(c) 5-Fluoro-3-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxaldehyde

A solution of (11b) (0.9 g, 5.4 mmol) in methanesulphonic acid (6 ml)was treated cautiously with hexamethylene tetramine (1.5 g, 10.8 mmol)and heated at 110° C. for 1 hour. The mixture was added to ice/water,extracted with ethyl acetate and the extracts dried and evaporatedgiving a yellow solid (0.78 g, 73%).

MS (+ve ion electrospray) m/z 196 (MH+)

(d) Title Compound

This was prepared from amine (1d) (0.21 g) and aldehyde (11c) (0.15 g)by the same reductive alkylation procedure as for Example 5, giving thefree base of the title compound as an oil (151 mg).

δH (CDCl₃): 1.55 (2H, m), 2.05 (2H, m), 2.25 (1H, m), 2.45 (2H, m), 2.70(1H, m), 2.85 (2H, m), 3.30 (1H, m), 3.40 (3H, s), 3.90 (2H, s), 3.94(3H, s), 5.45 (1H, dd), 6.68 (1H, d), 7.15 (1H, d), 7.20 (1H, d), 7.35(1H, dd), 7.62 (1H, d), 8.02 (1H, d), 8.75 (1H, d).

MS (+ve ion electrospray) m/z 481 (MH+).

This material was converted to the dioxalate salt (147 mg) by theprocedure of Example 1.

Example 12 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic Acid{1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-amideoxalate

(a) 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic Acid

2,3-Dihydro-benzo[1,4]dioxine-6-carboxaldehyde (2.03 g, 12.4 mmol), wasslurried in water (50 ml) at 80° C. Potassium permanganate (2.70 g, 17.1mmol) as a solution in water (50 ml) was added over 1 hour. The mixturewas then heated for a further 2 hours after which time the reactionmixture was basified with 10% aqueous potassium hydroxide. The resultingprecipitate was removed by filtration and washed with water (2×50 ml).The combined filtrates were acidified with concentrated hydrochloricacid and the resulting solid isolated by filtration and dried undervacuum. This provided the desired compound as a white solid (1.50 g,67%).

δH (CD₃OD): 4.32–4.24 (4H, m), 6.87 (1H, d), 7.52–7.47 (2H, m).

(b) Title Compound

Amine (1d) (127 mg, 0.44 mmol), carboxylic acid (12a) (76 mg, 0.44 mmol)and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (160 mg, 0.44 mmol) were dissolved inN,N-dimethylformamide (5 ml). To this solution triethylamine (0.12 ml,0.44 mmol) was added. The resulting mixture was stirred at roomtemperature for 10 hours after which time the volatiles were removed invacuo. The residue was partitioned between ethyl acetate (2×100 ml) andbrine (20 ml). The organic phase was dried over magnesium sulphate andthe volatiles again removed in vacuo. The resulting solid was subjectedto purification by chromatography on silica gel using a methanoldichloromethane solvent gradient. This afforded the desired amide as acolourless solid (76 mg, 39%).

δH (CDCl₃): 1.63–1.72 (2H, m), 2.05–2.19 (2H, m), 2.35–2.62 (3H, m),2.87–2.92 (2H, dd), 3.29–3.34 (1H, m), 3.94 (3H, s), 4.03 (1H, m),4.27–4.31 (4H, m), 5.48–5.51 (1H, dd), 5.97 (1H, d), 6.89 (1H, m), 7.18(1H, d), 7.28 (1H, m), 7.31 (1H, d), 7.36–7.40 (1H, dd), 7.64 (1H, d),8.04 (1H, d), 8.77 (1H, d).

MS (+ve ion electrospray) m/z 464 (MH+).

A solution of the solid (76 mg) in dichloromethane (1 ml) was added tooxalic acid (15 mg) in diethyl ether (10 ml) to generate the monooxalatesalt. The title compound was isolated by centrifugation, washing withdiethyl ether and subsequent drying in vacuo.

Example 136-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-3-methyl-3H-benzoxazole-2-thionedifumarate

(a) 3-Methyl-3H-benzooxazole-2-thione

3-Methyl-3H-benzoxazol-2-one (2.0 g, 13.4 mmol) was treated withdiphosphorus pentasulphide (4.0 g, 18 mmol). The mixture was heated to140° C. for 2 hours with vigorous stirring. The solid was cooled andthen extracted with toluene (2×50 ml). The toluene extract wasevaporated in vacuo and the residue partitioned between ethyl acetate(2×10 ml) and water (20 ml). The organic phases were combined and driedover magnesium sulfate. The volatiles were removed in vacuo to providethe desired compound as a white solid (1.77 g, 80%).

δH (CD₃OD): 3.51 (3H, s), 7.23–7.11 (4H, m).

(b) 3-Methyl-2-thioxo-2,3-dihydro-benzoxazole-6-carboxaldehyde.

Thione (13a) (527 mg, 3.20 mmol) and hexamethylenetetramine (817 mg, 6.4mmol) were dissolved in trifluoroacetic acid (5 ml) and heated at refluxfor 20 hours. The volatiles were removed in vacuo and the residue wastreated with ice/water (20 ml). The resultant mixture was stirred for 40minutes and then made basic with sodium carbonate. The solid wasisolated by filtration and washed with water then dried under vacuum.The solid was purified by column chromatography on silica gel elutingwith an ethyl acetate and hexane solvent gradient. This provided thedesired product as a white solid (136 mg, 20%).

δH (CD₃OD): 3.64 (1H, s), 7.40 (1H, d), 7.88–7.81 (2H, m), 9.92 (1H, s).

(c) Title Compound

Amine (1d) (150 mg, 0.5 mmol), was dissolved in dichloromethane (3 ml)and methanol (1 ml). To this solution was added activated 3A molecularsieves (1 g) and carboxaldehyde (13b) (96 mg, 0.5 mmol). The resultingsolution was heated at 50° C. for 6 hours and then the solution wascooled in an ice bath. Sodium borohydride (57 mg, 1.50 mmol) was added.The resulting slurry was stirred at room temperature for a further 10hours. The reaction mixture was quenched by the addition of water (2 ml)and the volatiles removed in vacuo. The residue was partitioned betweenethyl acetate (2×100 ml) and brine (20 ml). The organic phases werecombined and dried over magnesium sulphate. The volatiles were againremoved under reduced pressure and the resulting oil was subjected topurification on silica gel using a methanol/dichloromethane gradient.This afforded the free base of the title compound as a colourless oil(71 mg, 30%).

δH (CD₃OD): 1.47–1.60 (2H, m), 1.87–2.10 (2H, m), 2.14–2.26 (2H, m),2.50–2.71 (3H, m), 3.00–3.20 (2H, m), 3.65 (3H, s), 3.85 (2H, s), 3.94(3H, s), 5.55–5.60 (1H, dd), 7.22 (1H, d), 7.31–7.40 (4H, m), 7.66 (1H,d), 7.90 (1H, d), 8.64 (1H, d).

MS (+ve ion electrospray) m/z 479 (MH+).

To a solution of the oil (71 mg) in dichloromethane (10 ml) was addedfumaric acid (34 mg) in methanol:dichloromethane (1:1, 10 ml) togenerate the difumarate salt. The title compound was isolated byconcentration and drying in vacuo.

Example 146-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-3-methyl-3H-benzoxazol-2-onedioxalate

(a) 3-Methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxaldehyde

3-Methyl-3H-benzoxazol-2-one (2.0 g, 13.4 mmol) andhexamethylenetetramine (3.7 g, 26.8 mmol) were dissolved intrifluoroacetic acid (20 ml) and heated at reflux for 20 hours. Thevolatiles were removed in vacuo and the residue was treated with icewater (60 ml). The resultant mixture was stirred for 30 minutes and thenbasified with sodium carbonate. The solid was isolated by filtration,washed with water and then dried under vacuum. The solid was purified bycolumn chromatography on silica gel eluting with an ethyl acetate andhexane solvent gradient. This provided the aldehyde as a white solid(1.07 g, 45%).

δH (CDCl₃): 3.48 (3H, s), 7.10 (1H, d), 7.33 (1H, d), 7.80–7.76 (1H,dd), 9.95 (1H, s).

(b) Title Compound

Amine (1d) (120 mg, 0.4 mmol) and carboxaldehyde (14a) (71 mg, 0.4 mmol)were dissolved in dichloromethane (4 ml) and methanol (1 ml). To thissolution was added freshly activated 3A molecular sieves (1 g). Theresulting solution was stirred at room temperature for 5 hours and thencooled and sodium borohydride (46 mg, 1.2 mmol) was added. The resultingslurry was stirred at room temperature for a further 10 hours. Thereaction mixture was quenched by the addition of water (2 ml) and thevolatiles removed in vacuo. The residue was partitioned between ethylacetate (2×100 ml) and brine (20 ml). The organic phases were combinedand dried over magnesium sulphate. The volatiles were again removedunder reduced pressure and the resulting oil was subjected topurification on silica gel using a methanol and dichloromethanegradient. This afforded the free base of the title compound as acolourless oil (52 mg, 28%).

δH (CDCl₃): 1.45–2.59 (8H, m), 2.80–2.87 (2H, m), 3.24–3.28 (1H, m),3.40 (3H, s), 3.86 (2H, s), 3.93 (3H, s), 5.42–5.45 (1H, dd), 6.90 (1H,d), 7.15–7.18 (2H, m), 7.24 (1H, m), 7.35–7.40 (1H, dd), 7.64 (1H, d),8.03 (1H, d), 8.77 (1H, d).

MS (+ve ion electrospray) m/z 463 (MH+).

This was converted to the dioxalate salt by the method of Example 1.

Example 15 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid{1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-amideoxalate

(a) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride

4H-Benzo[1,4]thiazin-3-one (7.0 g) was added cautiously portionwise tochlorosulfonic acid (15 ml) at 0° C. over 20 minutes and the solutionwas stirred cold for 1 hour and then heated at 45° C. for 2 hours. Itwas cooled and poured slowly into iced-water. The product was collected,washed well with water and dried in vacuo to give a white solid (7.0 g).

δH (CDCl₃): 3.57 (2H, s), 7.53 (1H, d), 7.58 (1H, d), 7.69 (1H, dd),8.94 (1H, br s).

(b) Title Compound

The amine (1d) (0.10 g) in tetrahydrofuran (5 ml) and chloroform (5 ml)was treated with diisopropylethylamine (0.3 ml) and then the sulfonylchloride (15a) (0.092 g) was added portionwise at 0° C. The solution wasstirred at 0° C. for 1 hour and evaporated to dryness. Aqueous sodiumcarbonate was added and the mixture was extracted with chloroform, driedand evaporated. The product was chromatographed on silica gel(methanol/dichloromethane) to afford the free base as a foam (0.12 g).

δH (CDCl₃): 1.55–2.60 (8H, m), 2.75 (2H, m), 3.20 (2H, m), 3.50 (2H, s),3.90 (3H, s), 5.38 (1H, dd), 5.48 (1H, br s), 7.10 (1H, d), 7.25 (2H,m), 7.36 (1H, dd) 7.40 (1H, s), 7.60 (1H, d), 8.05 (1H, d), 8.75 (1H,d), 8.95 (1H, br s)

MS (+ve ion electrospray) m/z 529 (MH+).

This was converted to the oxalate salt in a similar method to that forExample 1.

Example 166-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-onedioxalate

A solution of the amine (2f) (0.15 g) and carboxaldehyde (6c) (0.105 g)in dichloromethane (3 ml) and methanol (3 ml) was treated with 3Amolecular sieves and the mixture was stirred at room temperature for 18hours. The solution was treated with sodium borohydride (56 mg) inportions and after 3 hours the solution was filtered and evaporated todryness. The product in water and chloroform was acidified with 2Mhydrochloric acid, then basified with sodium bicarbonate, extracted withchloroform, dried over sodium sulfate, and evaporated. It waschromatographed on silica gel (methanol/dichloromethane) to afford thefree base as a foam (0.13 g).

δH (CDCl₃): 1.45–2.10 (5H, m), 2.18 (1H, t), 2.40 (2H, m), 2.55 (1H, m),2.83 (1H, m), 3.10 (1H, dd), 3.30 (1H, m), 3.42 (2H, m), 3.80 (2H, s),4.03 (3H, s), 5.72 (1H, dd), 6.82 (1H, s), 7.00 (1H, d), 7.12 (1H, d)7.25 (1H, d), 7.80 (1H, d), 8.00 (1H, br s), 8.20 (1H, d), 8.78 (1H, d)

MS (+ve ion electrospray) m/z 480 (MH+).

This was converted to the dioxalate salt by the method of Example 1.

Example 17 4-Oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-sulfonicacid{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-amideoxalate

(a) 4-Oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-sulfonyl chloride

This was prepared from 4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepineby the method of Example (15a).

δH (CDCl₃): 2.76 (2H, t), 3.58 (2H, t), 7.75 (1H, d), 7.81 (1H, dd),7.86 (1H, d), 8.23 (1H, br s).

(b) Title Compound

This was prepared from amine (2f) and sulfonyl chloride (a) by themethod of Example (15b).

δH (CDCl₃): 1.70 (1H, m), 1.90 (1H, m), 2.30 (2H, m), 2.55 (2H, t), 2.70(2H, m), 2.90 (1H, m), 3.10 (2H, m), 3.30 (2H, m), 3.50 (2H, m), 4.00(3H, s), 5.75 (1H, dd), 7.10 (1H, d), 7.60–7.75 (4H, m), 8.20 (1H, d),8.50 (1 h, bs), 8.75 (1H, d).

MS (+ve ion electrospray) m/z 544 (MH+).

This was converted to the oxalate salt by a similar method to that ofExample 1

Example 18(R)-1-(6-Methoxy-quinolin-4-yl)-2-{4-[(6-nitro-benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-ethanoldioxalate

The title compound was prepared in the same manner as Example 1 using6-nitro-benzo[1,3]dioxole-5-carboxaldehyde as the aldehyde component.The crude reaction mixture was purified by chromatography on silica gelusing a methanol and dichloromethane gradient to afford the free base ofthe title product as a colourless oil (120 mg, 40%).

δH (CDCl₃): 1.40–1.60 (2H, m), 1.90–2.00 (2H, m) 2.20–2.60 (4H, m),2.80–2.85 (2H, m), 3.30 (1H, m), 3.90 (3H, s), 4.00 (2H, s), 5.45 (1H,dd), 6.10 (2H, s), 7.10 (1H, s), 7.18 (1H, d), 7.38 (1H, dd), 7.55 (1H,s), 7.65 (1H, d), 8.05 (1H, d), 8.78 (1H, d).

MS (+ve ion electrospray) m/z 481 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 19(R)-2-{4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanoldioxalate

(a) 2-(2-Iodo-6-methyl-pyridin-3-yloxy)-ethanol

2-Iodo-6-methyl-pyridin-3-ol (6.49 g, 27.6 mmol) was stirred in a 1Msolution of sodium hydroxide (30 ml). To this was added1-bromoethan-2-ol (3.91 ml, 55.20 mmol) dropwise at room temperature.The resulting solution was then heated to 100° C. and stirred for 2hours. The reaction mixture was cooled and then extracted intochloroform (2×100 ml). The organic phases were combined and extractedwith a solution of 1M sodium hydroxide (25 ml). The organic phase wasthen dried over magnesium sulfate and concentrated in vacuo. Thisprovided the desired product which was used without further purification(5.26 g).

(b) 6-Methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

The pyridine (19a) (6.52 g, 23.37 mmol) was dissolved inN,N′-dimethylformamide (30 ml). The solution was cooled to 0° C. andsodium hydride was added (1.12 g, 28.04 mmol). This was followed bycopper powder (0.62 g, 9.82 mmol) and copper sulphate (1.87 g, 11.69mmol). The resulting slurry was stirred at 100° C. under argon for 12hours after which time it was quenched with water (2 ml). The volatileswere removed under reduced pressure and the residue was subjected topurification on silica gel employing a methanol-dichloromethane solventgradient. This provided the desired compound as a brown semi-solid (480mg, 14%).

(c) 6-Bromomethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

The pyridine (19b) (192 mg, 1.27 mmol) was dissolved in carbontetrachloride (10 ml). To the resulting solution was addedN-bromosuccinimide (249 mg, 1.399 mmol). The solution was then heated toreflux and irradiated with a 200W desktop lamp. The irradiation wascontinued for 1 hour after which time the reaction mixture was cooledand the volatiles removed under reduced pressure. The residue waspurified on silica gel using an ethyl acetate-hexanes solvent gradient.This provided the desired compound as a white solid (13 mg; 4%).

(d) Title Compound

The amine (1d) (13 mg, 0.04 mmol) was dissolved inN,N′-dimethylformamide (3 ml). To this solution was added potassiumcarbonate (15 mg, 0.11 mmol) and pyridine (19c) (10 mg, 0.04 mmol). Theresulting suspension was stirred at room temperature for 48 hours. Thereaction mixture was concentrated under vacuum and the residue waspurified on silica gel using a methanol-dichloromethane gradient. Thisafforded the desired compound as a colourless oil (7 mg; 36%).

δH (CDCl₃): 1.55–1.75 (2H, m), 2.00–2.65 (7H, m), 2.85–2.91 (1H, m),3.25–3.30 (1H, m), 3.85 (2H, s), 3.94 (3H, s), 4.22–4.27 (2H, m),4.26–4.35 (2H, m), 5.57–5.60 (1H, m), 6.89 (1H, d), 7.20 (1H, d), 7.26(1H, d), 7.38 (1H, dd), 7.69 (1H, d), 8.03 (1H, d), 8.77 (1H, d).

MS (APCI+) m/z 451 (MH+).

This was converted to the dioxalate salt by the method of Example 1.

Example 207-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-1-H-pyrido[2,3-b][1,4]thiazin-2-onedioxalate

Method A

(a) 6-Methoxycarbonylmethylsulfanyl-5-nitro-nicotinic acid methyl ester

A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (1.0 g)[prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590–2594(1951)] in dichloromethane (10 ml) containing triethylamine (0.76 ml)was treated with mercapto-acetic acid methyl ester (0.441 ml) and thesolution was stirred at room temperature for 1 hour and evaporated todryness. Sodium bicarbonate solution was added and the mixture wasextracted with dichloromethane, dried (anhydrous sodium sulfate) andevaporated to afford a solid (1.0 g).

MS (+ve ion electrospray) m/z 287 (MH+).

(b) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic acidmethyl ester

The ester (20a) (1.0 g) in acetic acid (50 ml) was treated with ironpowder (10 g) and the mixture was stirred and heated at 60° C. for 1hour, cooled and filtered. The filtrate was evaporated, treated withsodium bicarbonate solution and extracted with warm chloroform. It wasdried (anhydrous sodium sulfate) and evaporated to give a white solid(0.85 g).

MS (+ve ion electrospray) m/z 225 (MH+).

(c) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic acid

The ester (20b) (2.8 g) was hydrolysed with aqueous sodium hydroxide intetrahydrofuran by the method of Example (6a) to afford a solid (2.5 g).

MS (−ve ion electrospray) m/z 209 (M−H⁻).

(d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]thiazin-2-one

The carboxylic acid (20c) (2.48 g) was reacted withisobutylchloroformate and sodium borohydride by the method of Example(6b) to afford a solid (1.3 g), after recrystallisation fromchloroform-methanol (9:1).

MS (+ve ion electrospray) m/z 197 (MH+).

(e) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde

The alcohol (20d) (1.22 g) was oxidised with manganese dioxide by themethod of Example (6c) to afford a solid (0.7 g).

MS (−ve ion electrospray) m/z 193 (M−H⁻).

Method B

(d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]thiazin-2-one

The ester (20b) (14 g, 0.0625 mole) in THF (300 mL) was cooled to 0° C.and treated dropwise with Super-hydride (lithium triethylborohydride)(1.0 M solution in THF, 218 mL, 0.218 mole). The resulting mixture wasstirred at 0° C. for 1 hr and quenched with saturated aqueous NH₄Cl (100mL). The solvent was removed in vacuo to afford material (8 g, 65%),which was not purified further.

MS (ES) m/z 197 (M+H)⁺.

(e) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde

The alcohol (20d-Method B) (8 g, 40 mmole) was dissolved in 1:1THF/CH₂Cl₂ (100 mL) and stirred with MnO₂ (36 g, 0.4 mole) at 60° C. for24 hr. The mixture was filtered through celite®, and the filtrate wasconcentrated in vacuo to afford a solid (3.5 g, 44%).

MS (ES) m/z 195 (M+H)⁺.

(f) Title Compound

The aldehyde (20e) (0.098 g) was reacted with amine (1d) by the Methodof Example (6d) to afford the free base as a foam (0.15 g)

δH (CD₃OD): 1.55 (2H, m), 1.96 (2H, br. d), 2.25 (2H, m) 2.45–2.80 (3H,m), 3.15 (2H, t), 3.60 (2H, s), 3.78 (2H, s)_(j) 3.95 (3H, s), 5.60 (1H,dd), 7.30 (1H, d), 7.42 (2H, m), 7.70 (1H, d), 7.90 (1H, d) 8.10 (1H,d), 8.68 (1H, d),

MS (+ve ion electrospray) m/z 480 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 216-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl)-piperidin-4-ylamino}-methyl)-2-(R/S)-methyl-4H-benzo[1,4]thiazin-3-onedioxalate

(a) 2-(R/S)-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid ethyl ester

3-Amino-4-mercapto-benzoic acid ethyl ester zinc salt (2:1) (6.4 g)[prepared from 3,3′-dinitro-4,4′-disulfanediyl-di-benzoic acid diethylester (M. Fuson J. Org. Chem. 13, 690 (1948)) by reaction with zinc inacetic acid containing HCl in dioxan at room temperature] was reactedwith chloroacetyl chloride by the method of Example (8b) to afford asolid (2.0 g) after chromatography on silica gel (chloroform).

MS (+ve ion electrospray) m/z 252 (MH+).

(b) 2-(R/S)-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid

The ester (21 a) (2.3 g) was hydrolysed with aqueous sodium hydroxide intetrahydrofuran by the method of Example (6a) to afford a solid (1.95g).

MS (−ve ion electrospray) m/z 222 (M−H⁻).

(c) 6-Hydroxymethyl-2-(R/S)-methyl-4H-benzo[1,4]thiazin-3-one

The carboxylic acid (21b) (1.95 g) was reacted withisobutylchloroformate and sodium borohydride by the method of Example(6b) to afford a solid (1.19 g).

MS (−ve ion electrospray) m/z 208 (M−H—).

(d)2-(R/S)-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde

The alcohol (21c) (1.15 g) was oxidised with manganese dioxide by themethod of Example (6c) to afford a solid (0.95 g).

MS (−ve ion electrospray) m/z 206 (M−H⁻).

(e) Title Compound

The aldehyde (21d) (0.13 g) was reacted with amine (1d; 90% ee) by theMethod of Example (6d) to afford the free base as a foam (0.10 g)

δH (CDCl₃): 1.45 (3H, d), 1.50 (2H, m), 1.90–2.70 (6H, m), 2.85 (2H, m),3.30 (1H, m), 3.52 (1H, q), 3.80 (2H, s), 3.90 (3H, s), 5.41 (1H, dd),6.85 (1H, s), 7.00 (1H, dd), 7.20 (1H, d) 7.25 (2H, m), 7.35 (1H, dd),7.65 (1H, d), 8.05 (1H, d), 8.15 (1H, brs), 8.78 (1H, d)

MS (+ve ion electrospray) m/z 493 (MH+).

The dioxalate salt was prepared by the same method as for Example 1.

Example 227-Fluoro-6-{{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-benzo[1,4]thiazin-3-one

(a) 2,4-Difluoro-benzoic acid, ethyl ester

A solution of 2,4-difluoro-benzoic acid (19.3 g) in dry ethanol (200 ml)was treated with gaseous hydrochloric acid for 0.25 hours, then heatedto reflux for 4 hours. Evaporation gave a white solid (22.7 g, 100%).

MS (APCI+) m/z 187 (MH+).

(b) 2,4-Difluoro-5-nitro-benzoic acid, ethyl ester

A solution of (22a) (5.33 g) in a mixture of concentratednitric/sulphuric acids (4 ml/4 ml) was stirred at 0° C. for 2 hours,then partitioned between dichloromethane and water. The dichloromethaneextract was washed with water, brine, dried and evaporated to give awhite solid (5.0 g).

MS (APCI+) m/z 232 (MH+).

(c) 2-Fluoro-4-methoxycarbonylmethylsulfanyl-5-nitro-benzoic acid, ethylester

A solution of (22b) (2.82 g, 12.2 mmol) in dichloromethane (50 ml) wastreated with triethylamine (2 ml) then at 0° C. with methylthioglycolate (1 ml). After 3 hours at 0° C. the mixture was evaporatedand chromatographed eluting with an ethyl acetate/hexane gradientaffording a yellow solid (2.05 g).

MS (APCI+) m/z 318 (ME+).

(d) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid,ethyl ester

A solution of (22c) (1.35 g, 4.3 mol) in acetic acid (50 ml) was treatedwith iron (2.4 g, 42.6 mmol) and heated at 60° C. for 3.5 hours. Themixture was filtered through Kieselguhr and partitioned between ethylacetate and water. The organic extract was washed with water severaltimes, dried and evaporated affording a white solid (1.02 g).

MS (APCI+) m/z 256 (MH+).

(e) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

A solution of (22d) (1 g, 4.2 mmol) in tetrahydrofuran/water (10 ml/10ml) was treated with sodium hydroxide (0.34 g, 8.4 mmol) and stirred atroom temperature for 7.5 hours. The mixture was acidified with 1Maqueous hydrochloric acid and evaporated to dryness giving a whitesolid.

MS m/z 226 (M−H).

(f) 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one

A suspension of acid (22e) (˜4.2 mmol) in tetrahydrofuran (30 ml) wastreated with triethylamine (0.7 ml, 5.03 mmol) then at 0° C. withisobutyl chloroformate (0.6 ml, 4.6 mmol). After 0.5 hour the mixturewas filtered into a vigorously-stirred solution of sodium borohydride(0.48 g, 12.6 mmol) in ice/water (˜10 ml). After 0.25 hour the mixturewas acidified with 1M aqueous hydrochloric acid and extracted with ethylacetate. Drying and evaporation afforded an oil (0.89 g).

MS (APCI+) m/z 214 (MH+).

(g) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde

A solution of (22f) (0.89 g) in dichloromethane/tetrahydrofuran (200ml/20 ml) was treated with manganese dioxide (1.3 g, 14.7 mmol) thenheated at 40° C. for 16 hours. The mixture was filtered throughKieselguhr and evaporated affording a brown solid (0.8 g) which waspurified by chromatography on silica eluting with an ethylacetate/hexane gradient giving a white solid (0.55 g).

MS (APCI+) m/z 212 (MH+).

(h) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.30 g, 0.99 mmole) in CH₂Cl₂ (25 mL) and dry ethanol (10 mL) atRT was added the aldehyde (22 g) (0.20 g, 0.95 mmole) and granularNa₂SO₄ (approximately 200 mg). After 36 h, the reaction was filteredthrough a sintered-glass funnel and the filtrate was concentrated. Theremaining residue was dissolved in dry ethanol and reacted with NaBH₄(0.04 g, 1.0 mmole). After 12 h at RT, the reaction was concentratedunder vacuum and the residue was dissolved in a mixture of H₂O (2 mL)and saturated aqueous NaHCO₃ (10 mL). The aqueous solution was extractedwith EtOAc (2×50 mL) and the combined organic phases were washed withbrine then were dried over Na₂SO₄. Flash chromatography on silica gel(9:1 CHCl₃/MeOH containing 5% NH₄OH) afforded the title compound (0.34g, 70%) as light yellow solid:

MS (ES) m/z 498 (M+H)⁺.

Example 23(R)-2-{4-[(7-Fluoro-2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol

(a) 7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde

A solution of 6-fluoro-2,3-dihydro-benzo[1,4]dioxine (prepared from6-amino-2,3-dihydro-benzo[1,4]dioxine according to the procedure of V.Daukas, P. Gaidelis, R. Martinkus, S. Urboniene, Chemija, 1999, 10 (1),59), (154 mg, 1 mmol) in dichloromethane (0.5 ml) was treated withdichloromethyl methyl ether (0.25 ml) at 0° C. under argon. Titaniumtetrachloride (0.45 ml) in dichloromethane (0.5 ml) was added over 0.25hours. The cooling bath was removed and the mixture was stirred atambient temperature for 1 hour before being quenched with water andextracted with ether. The ether extract was washed with aqueous sodiumbicarbonate and brine. Drying and evaporation afforded a brown oil whichwas purified by chromatography on silica (ethyl acetate/hexane)affording a clear oil (0.12 g).

MS (APCI+) m/z 183 (MH+).

(b) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.30 g, 1.0 mmole) in CH₂Cl₂ (25 mL) and dry ethanol (10 mL) at RTwas added aldehyde (23a) (0.18 g, 1.0 mmole) and granular Na₂SO₄(approximately 200 mg). After 36 h, the reaction was filtered through asintered-glass funnel and the filtrate was concentrated. The remainingresidue was dissolved in dry ethanol and reacted with NaBH₄ (0.04 g, 1.0mmole). After 12 h at RT, the reaction was concentrated under vacuum andthe residue was dissolved in a mixture of H₂O (2 mL) and saturatedaqueous NaHCO₃ (10 mL). The aqueous solution was extracted with EtOAc(2×50 mL) and the combined organic phases were washed with brine thenwere dried over Na₂SO₄. Flash chromatography on silica gel (9:1CHCl₃/MeOH containing 5% NH₄OH) afforded the title compound (0.34 g,73%) as a white solid:

MS (ES) m/z 469 (M+H)⁺.

Example 24(R)-2-{4-(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol

(a) 5-Benzyloxy-2-hydroxymethyl-1H-pyridin-4-one

A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojicacid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40mmol), concentrated aqueous (880) ammonia (100 ml), and ethanol (20 ml)was heated to reflux overnight. The mixture was allowed to cool to roomtemperature then filtered. The resultant solid was washed with ether anddried in vacuo (5.9 g).

MS (APCI+) m/z 232 (MH+).

(b) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol

A solution of (24a) (2 g, 8.7 mmol) in water (220 ml) containing sodiumhydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1g) for 4 hours. The mixture was filtered and evaporated to give a whitesolid. This solid was dissolved in N,N-dimethylformamide (8 ml) thentreated with potassium carbonate (2.9 g) and 1,2-dibromoethane (0.6 ml,7 mmol). The mixture was heated at 85° C. overnight. The cooled mixturewas evaporated onto silica and chromatographed eluting with 10–30%methanol in ethyl acetate affording a white solid (250 mg, 21%).

MS (APCI+) m/z 168 (MH+).

(c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde

A solution of (24b) (250 mg, 1.5 mmol) in dichloromethane (5 ml) wastreated with manganese dioxide (650 mg, 7.5 mmol). After 3 days themixture was filtered and evaporated affording a white solid (150 mg,61%).

MS (APCI+) m/z 166 (MH+).

(d) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.33 g, 1.1 mmole) in CH₂Cl₂ (25 mL) and dry ethanol (10 mL) at RTwas added aldehyde (24c) (0.18 g, 1.1 mmole) and granular Na₂SO₄(approximately 200 mg). After 36 h, the reaction was filtered through asintered-glass funnel and the filtrate was concentrated. The remainingresidue was dissolved in dry ethanol and reacted with NaBH₄ (0.04 g, 1.0mmole). After 12 h at RT, the reaction was concentrated under vacuum andthe residue was dissolved in a mixture of H₂O (2 mL) and saturatedaqueous NaHCO₃ (10 mL). The aqueous solution was extracted with EtOAc(2×50 mL) and the combined organic phases were washed with brine thendried over Na₂SO₄. Flash chromatography on silica gel (9:1 CHCl₃/MeOHcontaining 5% NH₄OH) afforded the title compound (0.25 g, 55%) as awhite solid:

MS (ES) m/z 452 (M+H)⁺.

Example 25(R)-1-(6-Methoxy-[1,5]naphthyridin-4-yl)-2-{4-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethanol

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.30 g, 1.0 mmole) in CH₂Cl₂ (25 mL) and dry ethanol (10 mL) at RTwas added 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde(prepared according to the procedure of WO 98/08840, 0.17 g, 1.0 mmole)and granular Na₂SO₄ (approximately 200 mg). After 36 h, the reaction wasfiltered through a sintered-glass funnel and the filtrate wasconcentrated. The remaining residue was dissolved in dry ethanol andreacted with NaBH₄ (0.04 g, 1.0 mmole). After 12 h at RT, the reactionwas concentrated under vacuum and the residue was dissolved in a mixtureof H₂O (2 mL) and saturated aqueous NaHCO₃ (10 mL). The aqueous solutionwas extracted with EtOAc (2×50 mL) and the combined organic phases werewashed with brine then were dried over Na₂SO₄. Flash chromatography onsilica gel (9:1 CHCl₃/MeOH containing 5% NH₄OH) afforded the titlecompound (0.37 g, 83%) as a white solid:

MS (ES) m/z 449 M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=4.5 Hz, 1H), 8.21 (d, J=9.0 Hz,1H), 7.80 (d, J=4.5 Hz, 1H), 7.12 (m, 2H), 6.47 (d, J=7.3 Hz, 11H), 5.74(m, 1H), 4.77 (br s, 1H), 4.04 (s, 3H), 3.70 (s, 2H), 3.38 (m, 2H), 3.24(m, 1H), 3.08 (m, 1H), 2.79 (m, 2H), 2.71 (t, J=6.3 Hz, 2H), 2.57 (m,H), 2.40 (m, 2H), 2.17 (m, 1H), 1.91 (br m, 2H).

Example 26(R)-1-(6-Methoxyquinolin-4-yl)-2-{4-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethanol

To a stirred solution of the mono hydrochloride salt of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl) ethanol (1d)(0.34 g, 1.0 mmole) in CH₂Cl₂ (25 mL) and dry ethanol (10 mL) at RT wasadded 5,6,7,8-tetrahydro[1,8]naphthyridine-2-carboxaldehyde (preparedaccording to the procedure of WO 98/08840, 0.17 g, 1.0 mmole),triethylamine (0.10 g, 1.0 mmole), and granular Na₂SO₄ (approximately200 mg). After 36 h, the reaction was filtered through a sintered-glassfunnel and the filtrate was concentrated. The remaining residue wasdissolved in dry ethanol and reacted with NaBH₄ (0.04 g, 1.0 mmole).After 12 h at RT, the reaction was concentrated under vacuum and theresidue was dissolved in a mixture of H₂O (2 mL) and saturated aqueousNaHCO₃ (10 mL). The aqueous solution was extracted with EtOAc (2×50 mL)and the combined organic phases were washed with brine then were driedover Na₂SO₄. Flash chromatography on silica gel (9:1 CHCl₃/MeOHcontaining 5% NH₄OH) afforded the title compound (0.31 g, 69%) as awhite solid:

MS (ES) m/z 448 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=4.5 Hz, 1H), 8.03 (d, J=9.2 Hz,1H), 7.64 (d, J=4.5 Hz, 1H), 7.35 (d, J=6.6 Hz, 1H), 7.18 (m, 1H), 7.10(d, J=7.0 Hz, 1H), 6.46 (d, J=7.3 Hz, 1H), 5.42 (m, 1H), 4.77 (m, 1H),3.93 (s, 3H), 3.70 (s, 2H), 3.38 (m, 2H), 3.20 (m, 1H), 2.83 (m, 2H),2.71 (t, J=6.3 Hz, 2H), 2.58 (m, 1H), 2.47 (m, 1H), 2.40 (m, 1H), 2.20(m, 1H), 1.91 (br m, 2H).

Example 276-[({(3S,4S)-3-Hydroxy-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)₄H-benzo[1,4]thiazin-3-oneand6-[({(3R,4R)-3-Hydroxy-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)-4H-benzo[1,4]thiazin-3-one

(a) tert-Butyl 3,6-dihydro-2H-pyridine-1-carboxylate

1,2,3,6-tetrahydropyridine (15.0 g, 180 mmole) was added to a 10%aqueous solution of Na₂CO₃ (50 mL) and the solution was cooled to 0° C.Di-tert-butyl dicarbonate (39.8 g, 182 mmole) was added in portions over15 min with vigorous stirring. The solution was stirred at 0° C. for 1hr and then warmed to room temperature and stirred for an additional 18hr. The reaction solution was partitioned between Et₂O and saturatedNaCl solution. The ether layer was dried over Na₂SO₄ and concentrated invacuo to give an oil (31.80 g, 96%), which needed no furtherpurification.

MS (ES) m/z 184 (M+H)⁺.

(b) tert-Butyl 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate

A solution of (27a) (15.0 g, 81.9 mmole) in CH₂Cl₂ (150 mL) was treatedwith a solution of metachloroperbenzoic acid (18.36 g, 106.4 mmole) inCH₂Cl₂ (300 mL) which was added over 30 minutes at 0° C. The solutionwas allowed to warm to room temperature and stirred for 18 hr. Thereaction solution was washed with 5% aqueous K₂CO₃ and saturated NaClsolution, then dried over Na₂SO₄ and concentrated in vacuo to yield anoff-white solid. This was flash chromatographed on silica gel (20%EtOAc/hexanes) to yield a white solid (12.80 g, 78%).

MS (ES) m/z 200 (M+H)⁺.

(c) tert-Butyl (±)-trans-4-benzylamino-3-hydroxypiperidine-1-carboxylate

The ester (27b) (13.24 g, 66.5 mmole) was combined with benzylamine(14.53 mL, 133 mmole) and stirred while heating at 115° C. The reactionwas allowed to stir for 8 hr at 115° C. and then allowed to cool toambient temperature. EtOAc was added and the organic layer was washedsequentially with H₂O and saturated NaCl solution. The organic layer wasdried over Na₂SO₄ and concentrated to yield a yellow solid (19.31 g,95%): LCMS: m/z 307 (M+H)⁺. This mixture of regioisomers waschromatographed (preparative HPLC) on Lichrosphere silica gel 60A; 12 u,100 mm ID×250 mm L; 70:30:0.5 hexanes:THF:diethylamine; 500 mL/min; uvdetection 254 nm; 4.5 g mixture per injection. The products, tert-butyl(±)-trans-3-benzylamino-4-hydroxy-piperidine-1-carboxylate andtert-butyl (±)-trans-4-benzylamino-3-hydroxy-piperidine-1-carboxylate,as assigned by NMR, were obtained in a 3:1 ratio with retention times of8.4 min and 6.5 min, respectively.

(d) tert-Butyl (±)-trans-4-amino-3-hydroxypiperidine-1-carboxylate

A solution of the ester (27c) (0.5 g, 1.63 mmole) in EtOH (40 mL) wastreated with 10% palladium on carbon (catalytic) and hydrogenated in aParr bottle for 6 hr at 40 psi. The solution was filtered through a plugof celite®, and the filter pad was washed with EtOH. The filtrate wasconcentrated to yield a yellow oil (0.35 g, 99%). No furtherpurification was required.

MS (ES) m/z 217 (M+H)⁺.

(e) tert-Butyl(±)-trans-3-hydroxy-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)amino]piperidine-1-carboxylate

A solution of amine (27d) (0.35 g, 1.62 mmole) in CH₂Cl₂ (10 mL) wastreated with 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde(6c) (0.34 g, 1.78 mmole). The solution was sonicated for 5 min and thenallowed to stir at ambient temperature for 5 hr. Na(OAc)₃BH (0.52 g,2.43 mmole) was added and the solution was stirred at ambienttemperature for 2 hr. The reaction was diluted with EtOAc and washedwith saturated aqueous NaHCO₃ solution, H₂O, and saturated aqueous NaClsolution. The organic layer was dried over Na₂SO₄ and concentrated toyield an off-white solid. This was flash chromatographed on silica gel(90:10:1 CHCl₃/MeOH/NH₄OH) to yield a white solid (0.31 g, 48%).

MS (ES) m/z 394 (M+H)⁺.

(f)(±)-trans-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)amino]piperidine

A solution of (27e) (0.30 g, 0.76 mmole) in CH₂Cl₂ (3 mL) was treatedwith 4.0 N HCl/dioxane (5 mL). The solution was allowed to stir for 30min and then concentrated. MeOH was added and the solution was againconcentrated to remove any excess HCl. The remaining solid was dissolvedin MeOH (5 mL) and treated with MP-Carbonate resin (1.00 g, 2.87 mmole).The solution was then filtered and concentrated to yield a white solid,(0.24 g, 100%). No further purification was necessary.

MS (ES) m/z 294 (M+H)⁺.

(g) Title Compound

A solution of the amine (27f) (0.23 g, 0.784 mmole) in DMF (4 mL) wastreated with the oxirane (1b) (0.158 g, 0.784 mmole) and LiClO₄ (0.083g, 0.784 mmole and stirred at 100° C. for 16 hr. EtOAc was added aftercooling to room temperature and the solution was washed with water (3×)and saturated aqueous NaCl solution. The organic layer was dried overNa₂SO₄ and concentrated to yield an oil. This was flash chromatographedon silica gel (90:10:1 CHCl₃/MeOH/NH₄OH) to yield the title compound asa 1:1 diasterereomeric mixture (0.217 g, 56%), as a tan solid.

MS (ES) m/z 495 (M+H)⁺.

The individual diastereomers of the 1:1 mixture were separated via HPLCon a Chiralcel OD column, 250×20 mm ID;75:25:0.1-hexanes:ethanol:diethylamine; 17.5 mL/min; uv detection at 214& 254 nm; retention times of 11.6 min and 17.9 min.

Example 287-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-1H-pyrido[2,3-b][1,4]thiazin-2-one

A solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.1 g, 0.33 mmole) and aldehyde (20e) (65 mg, 0.3 mmole) in CH₂Cl₂(5 mL) and MeOH (15 mL) was treated with 3 Å molecular sieves, and themixture was stirred at room temperature for 18 hr. NaBH₄ (18 mg, 0.48mmole) was added portionwise, and the resulting mixture was stirred foran additional 3 hr, then was filtered. The filtrate was concentrated todryness in vacuo, and the residue was partitioned between H₂O and CHCl₃.The mixture was made acidic with 2 M HCl, then was made basic withNaHCO₃. Extraction with CHCl₃, drying (Na₂SO₄), and concentration invacuo left a residue that was purified by flash chromatography on silicagel (MeOH/CH₂Cl₂). The title compound (0.04 g, 27%) was obtained as afoam.

MS (ES) m/z 481 (M+H)⁺.

Example 297-{{1-[(R)-2-Hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl}-2,3-dihydro-5H-benzo[b][1,4]thiazepine-4-one,diacetate

(a) Methyl 3-(4-formyl-2-nitrophenylsulfanyl)propionate

To a solution of 4-chloro-3-nitrobenzaldehyde (2.60 g, 0.014 mole) andmethyl 3-mercaptopropionate (1.92 g, 0.016 mole) in DMF (10 mL) wasadded anhydrous K₂CO₃ (2.07 g, 0.016 mole). After stirring at ambienttemperature for 16 hr, the reaction was quenched with ice water. Theprecipitated product was collected by suction filtration, washed wellwith water, and dried in vacuo to give a bright yellow solid (3.65 g,97%).

MS (ES) m/z 270.1 (M+H)⁺.

(b) 4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxaldehyde

To a solution of the ester (29a) (3.65 g, 0.014 mole) in glacial AcOH(100 mL) was added iron powder (7.9 g, 0.141 g atom). After heating at60° C. for 12 hr, the warm mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and aqueous NaCl, and the organic layer was dried (MgSO₄).Purification by flash column chromatography on silica gel (gradientelution: 4:1, 2:1, 1:1 EtOAc/hexanes) yielded a light yellow solid(0.553 g, 20%).

MS (ES) m/z 208.0 (M+H)⁺.

(c) Title Compound

A solution of the aldehyde (29b) (0.104 g, 0.50 mmole) and(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl)ethanol (1d)(0.162 g, 0.54 mmole) were stirred together in 1:1 MeOH/dichloroethane(1.5 mL) at ambient temperature for 24 hr. The intermediate imine wastreated with NaBH₄ (0.093 g, 2.46 mmole) and the reaction was stirredfor an additional 16 hr. The solvents were removed under reducedpressure and the residue was partitioned between CH₂Cl₂ and aqueousNaCl, and the organic layer was dried (MgSO₄). Purification by flashcolumn chromatography on silica gel (gradient elution: 1:9 to 1:4MeOH/CH₂Cl₂ with 1% glacial AcOH) yielded the title compound (37.4 mg,15%) as an amorphous yellow solid.

MS (ES) m/z 493.2 (M+H)⁺.

Example 306-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one,dihydrochloride

(a) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol(400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13mole) was added at room temperature. The mixture was stirred for 30 min,then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was addedslowly. The reaction was then stirred at 0° C. for 30 min, then wasquenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo toafford material (30 g, 96%), which was used without furtherpurification.

MS (ES) m/z 219.0 (M+H)⁺.

(b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

The hydroxypyridine (30a) (30 g, 0.14 mole) was suspended in acetone(200 mL), and potassium carbonate (39 g, 0.28 mole) was added, followedby ethyl bromoacetate (15.7 mL, 0.14 mmole). The reaction was heated atreflux for 10 hr, then was cooled to room temperature and diluted withEt₂O. The precipitate was removed by suction filtration, and thefiltrate was concentrated in vacuo to afford material (38 g, 89%), whichwas used without further purification.

MS (ES) m/z 305.0 (M+H)⁺.

(c) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

The nitropyridine (30b) (38 g, 0.125 mole) was dissolved in glacial AcOH(150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture wasmechanically stirred and heated at 90° C. for 5 hr, then was cooled toroom temperature and diluted with EtOAc (300 mL). The mixture wasfiltered through a pad of silica gel and the filtrate was concentratedin vacuo and the residue recrystallized from MeOH (15 g, 52%).

MS (ES) m/z 229.0 (M+H)⁺.

(d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The bromopyridine (30c) (6.0 g, 26.3 mmole) andtrans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph₃P)₄Pd(230 mg, 0.2 mmole) was added, followed by a solution of potassiumcarbonate (6.9 g, 50 mmole) in H₂O (20 mL). The reaction was heated atreflux under argon overnight, then was cooled to room temperature anddiluted with EtOAc (200 mL). The solution was washed sequentially withH₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The solidresidue was purified by flash chromatography on silica gel (5–10%EtOAc/CHCl₃) to afford a solid (2.5 g, 38%).

MS (ES) m/z 253.0 (M+H)⁺.

(e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

The pyridine (30d) (1.2 g, 4.8 mmole) was dissolved in CH₂Cl₂ (200 mL)and the solution was cooled to −78° C. Ozone was bubbled through thesolution with stirring until a pale blue color appeared, then the excessozone was removed by bubbling oxygen through the solution for 15 min.Dimethylsulfide (1.76 mL, 24 mmole) was added to the solution, and thereaction was stirred at −78° C. for 3 hr, then at room temperatureovernight. The solvent was removed in vacuo, and the residue wastriturated with Et₂O (50 mL). The collected solid was washed withadditional Et₂O and dried to afford a solid (700 mg, 82%).

MS (ES) m/z 179.0 (M+H)⁺.

(f) Title Compound

(R)-2-(4-Amino-piperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol(2f) (254 mg, 0.84 mmole), aldehyde (30e), (150 mg, 0.84 mmole), and acatalytic amount of 4 Å molecular sieves were combined in DMF (2 mL),and the mixture was stirred overnight. MeOH (3 mL) and sodiumborohydride (48 mg, 1.26 mmole) were added, and the reaction mixture wasstirred at room temperature for 2 hr. The solvent was removed in vacuo,and the residue was dissolved in a mixture of 1:2 MeOH/EtOAc (5 mL). Asolution of HCl in Et₂O (1.0 M, 1.7 mL, 1.7 mmole) was added, and theprecipitated solid was collected, washed with EtOAc, and dried to affordthe title compound (75 mg, 17%).

MS (ES) m/z 465.0(M+H)⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.80 (d, J=4.6 Hz, 1H), 8.24 (d, J=9.1 Hz,1H), 7.94 (d, J=4.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.27 (d, J=9.1 Hz,1H), 7.13 (d, J=8.0 Hz, 1H), 6.20 (d, J=9.3 Hz, 1H), 4.70 (s, 2H), 4.34(s, 2H), 4.21 (m, 1H), 4.14 (s, 3H), 3.51–3.81 (m, 3H), 3.16–3.39 (m,3H), 2.40–2.54 (m, 2H), 2.20–2.45 (m, 2H)

Example 316-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}4H-pyrido[3,2-b][1,4]thiazin-3-one,hydrochloride

(a) Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 ml) in DMF (48 ml) wasice-cooled and treated with sodium hydride (540 mg of a 60% dispersionin oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3 g)(T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623–4633) was addedand the mixture stirred 16 hours at room temp. The solution was dilutedwith EtOAc (1 liter), washed with water (3×300 ml), dried and evaporatedto about 10 ml. The white solid was filtered off and washed with alittle EtOAc to give a solid (0.95 g).

MS (APCI⁻) m/z 223 ([M−H]⁻, 100%)

(b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid

A solution of the ester (31a) (788 mg) in dioxan (120 ml)/water (30 ml)was treated dropwise over 2 hours with 0.5M NaOH solution (8 ml) andstirred overnight. After evaporation to approx. 3 ml, water (5 ml) wasadded and 2N HCl to pH4. The precipitated solid was filtered off, washedwith a small volume of water and dried under vacuum to give a solid (636mg).

MS (APCI⁻) m/z 209 ([M−H]⁻, 5%), 165([M—COOH]⁻, 100%)

(c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of the carboxylic acid (31 b) (500 mg) in THF (24 ml) withtriethylamine (0.396 ml) was cooled to −10° C. and isobutylchloroformate (0.339 ml) added. After 20 mins. at this temp. thesuspension was filtered through kieselguhr into an ice-cooled solutionof sodium borohydride (272 mg) in water (8 ml), the mixture stirred 30mins. and the pH reduced to 7 with dilute HCl. Solvent was evaporatedand the residue triturated under water. The solid was filtered and driedunder vacuum to give a white solid (346 mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 50%), 165(100%)

(d) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of the alcohol (31 c) (330 mg) in dichloromethane (30 ml)/THF(30 ml) was treated with manganese dioxide (730 mg) and stirred at roomtemp. Further manganese dioxide was added after 1 hour (730 mg) and 16hours (300 mg). After a total of 20 hours the mixture was filteredthrough kieselguhr and the filtrate evaporated. The solid was trituratedunder EtOAc/hexane 1:1 and filtered off to give a solid (180 mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 95%), 165(100%)

(e) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.234 g, 0.77 mmole) in CH₂Cl₂ (3 mL) and dry methanol (3 mL) atRT was added the aldehyde (31d) (0.100 g, 0.52 mmole), and granularNa₂SO₄ (approximately 200 mg). After 12 h NaBH₄ (0.08 g, 2.0 mmole) wasadded and the mixture was stirred for 4 hours, then poured intosaturated aqueous sodium bicarbonate solution (10 mL) and extracted withchloroform (3×10 mL). The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The residue was dissolved inmethanol (3 mL) and diluted with ethyl acetate (3 mL). While stirring asolution of 1.0 M HCl in ether (0.5 mL) was added dropwise. The productwas collected by suction filtration, washed with ethyl acetate thenEt₂O, and dried under vacuum to afford the monohydrochloride salt of thetitle compound (0.150 g, 57%) as an off-white solid.

MS (ES) m/z 481 (M+H)⁺.

Example 32(R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b[1,4]oxazin-6-ylmethyl)-amino]-piperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl}-ethanol,hydrochloride

(a) 6-((E)-Styryl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (30d) (350 mg, 1.54mmole), was dissolved in anhydrous THF (10 mL) and the solution wascooled to 0° C. A solution of LiAlH₄ in THF (1.0 M, 1.54 mL, 1.54 mmole)was added dropwise at 0° C. The reaction was then warmed to roomtemperature and stirred for 2 hr. H₂O (0.06 mL) was added dropwise andmixture was stirred for 5 min, then 15% sodium hydroxide (0.06 mL) wasadded followed by H₂O (0.18 mL). The mixture was stirred overnight, thenwas diluted with Et₂O and filtered through celite®. The filtrate wasconcentrated and the residue was purified by flash chromatography onsilica gel (5% EtOAc/CHCl₃) to afford the product (200 mg, 55%).

MS (ES) m/z 239.0 (M+H)⁺.

(b) 3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

OsO₄ (4% solution in water, 0.25 mL), H₂O (1 mL), and sodium periodate(539 mg, 2.5 mmole) were added to a solution of the pyridooxazine (32a)(200 mg, 0.84 mmole) in 1,4-dioxane (5 mL). The reaction was stirred atroom temperature for 5 hr, then was diluted with H₂O (5 mL). The mixturewas extracted with chloroform, and the combined organic layers wereconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (5% EtOAc/CHCl₃) to afford the product (65 mg, 47%).

MS (ES) m/z 165.0 (M+H)⁺.

(c) Title Compound

(R)-2-(4-Aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (111 mg, 0.37 mmole), aldehyde (32b) (55 mg, 0.33 mmole), andanhydrous Na₂SO₄ powder (a catalytic amount) were combined in CH₂Cl₂ (2mL), and the mixture was stirred overnight. MeOH (3 mL) and NaBH₄ (13mg, 0.33 mmole) were added, and the reaction was stirred at roomtemperature for 2 hr. The solvent was removed in vacuo, and the residuewas partitioned between H₂O and CHCl₃. The organic layer was washed withbrine and dried (Na₂SO₄). The solvent was removed in vacuo, and theresidue was dissolved in a mixture of 1:2 MeOH/EtOAc (3 mL). A solutionof HCl in Et₂O (1.0 M, 0.33 mL, 0.33 mmole) was added, and theprecipitated solid was collected, washed with EtOAc, and dried to affordthe title compound (40 mg, 25%).

¹H NMR (400 MHz, CD₃OD) δ 9.04 (d, J=5.4 Hz, 1H), 8.42 (d, J=9.3 Hz,1H), 8.33 (d, J=5.3 Hz, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.23 (d, J=7.8 Hz,1H), 6.89 (d, J=7.9 Hz, 1H), 6.33 (d, J=8.4 Hz, 1H), 4.35 (s, 2H), 4.21(s, 3H), 4.15 (m, 1H), 3.51–3.85 (m, 6H), 3.30–3.58 (m, 4H), 2.40–2.54(m, 2H), 2.20–2.40 (m, 2H).

MS (ES) m/z 451.0 (M+H)⁺.

Example 337-Bromo-6-{{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}4H-pyrido[3,2-b][1,4]thiazin-3-one

(a) Methyl 6-amino-3,5-dibromopyridine-2-carboxylate

A solution of methyl 6-amino-3-bromopyridine-2-carboxylate (20.62 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623–4633) in chloroform(570 ml) was treated dropwise over 2 hours with bromine (4.62 ml) inchloroform (115 ml) and stirred 16 hours. The solution was washed withexcess aqueous sodium bicarbonate, dried and evaporated. Crystallisationfrom EtOAc/hexane gave a solid (13.5 g).

MS (APCI⁺) m/z 309, 311, 313 (MH⁺, 70%), 295, 297, 299 (100%)

(b) Methyl7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

This was prepared from (33 a) (12.75 g), analogously to methyl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (Example31a). Yield 5.85 g.

MS (APCI⁺) m/z 303, 305 (MH⁺, 30%), 271, 273 (100%)

(c) 7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid

This was prepared from (33b) analogously to3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid(Example 31b) (73%).

MS (APCI⁻) m/z 287, 289 ([M−H]⁻, 3%), 243, 245 ([M—COOH]⁻, 100%)

(d)7-Bromo-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

This was prepared from (33c) analogously to6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (Example31c) (80%).

MS (APCI⁺) m/z 275, 277 (M+, 20%), 257, 259 (100%)

(e)7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A mixture of the alcohol (33d) (518 mg), manganese dioxide (870 mg), THF(45 ml) and 1,2-dichloroethane (45 ml) was heated at 60° C. under argon.Further manganese dioxide was added after 4 hours (870 mg) and 20 hours(600 mg). After a total of 30 hours filtration through kieselguhr andevaporation of solvent gave the product (320 mg).

MS (APCI⁻) m/z 271, 273 ([M−H]⁻, 40%), 152 (100%)

(f) Title Compound

A solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl)ethanol (1d) (55mg, 0.138 mmole) in CH₂Cl₂ (2 mL) and EtOH (0.2 mL) was treated withanhydrous Na₂SO₄ (100 mg) and aldehyde (33e) (50 mg, 0.18 mmole). Theresulting solution was stirred at room temperature for 14 hr, thensodium triacetoxy borohydride (57 mg, 0.27 mmole) was added. Theresulting slurry was stirred at room temperature for a further 10 hr,then was quenched by the addition of water (2 mL) and the volatiles wereremoved in vacuo. The residue was partitioned between EtOAc (2×20 mL)and brine (5 mL). The organic phases were combined, dried (MgSO₄), andconcentrated in vacuo. The resulting oil was purified by flashchromatography on silica gel (gradient: 0–10% MeOH/CH₂Cl₂) to afford thetitle compound (35 mg, 35%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.69 (d, 1H), 8.21 (d, 1H), 7.81 (d, 1H), 7.76(s, 1H), 7.12 (d, 1H), 5.21–5.30 (dd, 1H), 4.16 (s, 3H), 3.96 (s, 2H),3.29–3.39 (m, 1H), 3.08–3.15 (dd, 1H), 2.29–2.61 (m, 4H), 1.50–2.5 (m,8H).

MS (ES) m/z 559, 561 (M+H)⁺.

Example 347-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-1H-pyrido[3,4-b][1,4]thiazin-2-one

(a) 5-Fluoro-2-picoline N-oxide

Preparation of 5-fluoro-2-picoline was based on E. J. Blanz, F. A.French, J. R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13,1124–1130. 5-Amino-2-picoline (12.5 g) in ethanol (105 ml) and 50%fluoroboric acid (44.5 ml) was stirred at −5° C. and treated dropwiseover 45 mins. with n-butyl nitrite (31.25 ml). The solution wasmaintained at this temp. for 3 hours, treated with ether (100 ml,precooled to −20° C.) and the solid filtered off, quickly transferred toa flask and covered with hexane (precooled to −20° C.). After allowingto warm to approx. 20° C. and standing for 3 days the hexane wasdecanted and 2M NaOH solution added until basic (pH10). The mixture wasfiltered and the filtrate extracted with dichloromethane (10×200 ml).The organic solution was dried, evaporated to 200 ml and treated withm-chloroperbenzoic acid (26.5 g). After stirring 16 hours the solutionwas washed with excess aqueous sodium bicarbonate and the aqueousre-extracted with dichloromethane (10×200 ml). The organic fraction wasdried and evaporated and the residue chromatographed (15% EtOH/EtOAc) togive the product (5.5 g).

MS (APCI⁺) m/z 128 (MH⁺, 100%)

(b) 5-Fluoro-4-nitro-2-picoline N-oxide

The picoline N-oxide (34a) (2.12 g) was treated with an ice-cooledmixture of filming nitric acid (7.1 ml) and conc. sulfuric acid (70.1ml), heated at 35–40° C. for 1 hour and 65–70° C. for 5.5 hours, cooledand ice (45 g) added. 10M NaOH was added to pH10 and the mixtureextracted with EtOAc (3×30 ml). The organic fraction was dried andevaporated to give a yellow solid (2.16 g).

MS (APCI⁺) m/z 173 (MH⁺, 30%), 127 (100%)

(c) 5-Ethoxycarbonylmethylthio-4-nitro-2-picoline N-oxide

Ethyl 2-mercaptoacetate (1.51 g) in dioxan (15.6 ml) under argon wastreated with sodium hydride (550 mg of a 60% dispersion in oil) andstirred 4 hours. The picoline N-oxide (34b) (2.16 g) was added andstirring continued 3 days. Water (50 ml) was added and the mixtureextracted with chloroform (3×50 ml). The organic fraction was dried andevaporated to give a yellow solid (3.31 g).

MS (APCI⁺) m/z 273 (MH⁺, 80%), 125 (100%)

(d) 2-Acetoxymethyl-5-ethoxycarbonylnethylthio-4-nitropyridine

A solution of the picoline N-oxide (34c) (3.31 g) in acetic anhydride(43 ml) was heated to 80° C. for 6 hours, evaporated, xylene (100 ml)added and evaporated. Chromatography of the residue (eluent EtOAc/hexane1:1) gave the product (1.03 g).

(e) 7-Acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine

A solution of the nitropyridine (34d) (1.03 g) in glacial acetic acid(27.5 ml) was treated with iron powder (1.75 g), stirred at 60° C. for 3hours, filtered through kieselguhr and evaporated to dryness. Saturatedaqueous sodium bicarbonate (300 ml) was added and extracted with EtOAc(3×200 ml), the organic fraction was dried and evaporated. The residuewas redissolved in acetic acid (30 ml), heated to 100° C. for 24 hours,evaporated and chromatographed (eluent EtOAc/hexane 1:1) to give theproduct (340 mg).

MS (APCI⁻) m/z 237 ([M−H]⁻, 90%), 195 (100%)

(f) 7-Hydroxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine

A solution of the ester (34e) (340 mg) in dioxan (9 ml) was treateddropwise over 2 hours with 0.5M NaOH (3.7 ml), stirred 18 hours andevaporated. Water (10 ml) was added and the white solid filtered off,washed with water and dried under vacuum to give a solid (231 mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 100%)

(g) 2-Oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carbaldehyde

A mixture of the alcohol (34f) (226 mg), manganese dioxide (600 mg), THF(22.5 ml) and 1,2-dichloroethane (22.5 ml) was heated at 65° C. for 18hours under argon. Filtration through kieselguhr and evaporation ofsolvent gave an off-white solid (173 mg).

MS (APCI⁻) m/z 193 ([M−H]⁻, 100%).

(h) Title Compound

A solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl)ethanol (1d) (78mg, 0.26 mmole) in CH₂Cl₂ (3 mL) and EtOH (0.2 mL) was treated withanhydrous Na₂SO₄ (100 mg) and aldehyde (34 g) (50 mg, 0.26 mmole). Theresulting solution was stirred at room temperature for 14 hr and thensodium triacetoxy borohydride (82 mg, 0.39 mmole) was added. Theresulting slurry was stirred at room temperature for a further 10 hr,then was quenched by the addition of water (2 mL) and the volatiles wereremoved in vacuo. The residue was partitioned between EtOAc (2×20 mL)and brine (5 mL). The organic phases were combined, dried (MgSO₄), andconcentrated in vacuo. The resulting oil was purified by flashchromatography on silica gel (gradient: 0–10% MeOH/CH₂Cl₂) to afford thetitle compound (35 mg, 28%) as a colorless oil:

¹H NMR (400 MHz, CDCl₃) δ 8.78 (d, 1H), 8.40 (s, 1H), 8.21 (d, 1H), 7.78(d, 1H), 7.12 (d, 1H), 6.90 (s, 1H), 5.70–5.80 (dd, 1H), 5.21–5.30 (dd,1H), 4.03 (s, 3H), 3.89 (s, 2H), 3.39–3.49 (m, 2H), 3.04–3.10 (dd, 1H),2.83–2.90 (d, 1H), 2.18–2.70 (m, 4H), 1.50–2.05 (m, 4H).

MS (ES) m/z 481 (M+H)⁺.

Example 35(R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,dihydrochloride

(a) (3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-yl)-methanol

A solution of methyl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (31a) (1.0g) in dry tetrahydrofuran (170 ml) was treated with a 1M solution oflithium aluminium hydride in ether (14 ml) and the mixture was heatedunder reflux for 18 hours. It was cooled and a slight excess of 2Nsodium hydroxide was added followed by chloroform and anhydrous sodiumsulphate and the mixture was stirred for 30 minutes and filtered. Thesolution was evaporated to dryness to give a semi-solid (0.482 g)

MS (APCI⁺) m/z 183 (MH⁺)

(b) 3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

The alcohol (35a) (0.482 g) in dry dichloromethane (50 ml) was stirredwith manganese dioxide (1.2 g) for 18 hours and the mixture wasfiltered. The filtrate was evaporated and chomatographed on silica gel,eluting with methanol-dichloromethane (1:50) to afford a yellow solid(0.24 g)

(c) Title Compound

(R)-2-(4-Aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl)ethanol (1 d)hydrochloride (172 mg, 0.51 mmole), aldehyde (35b) (92 mg, 0.51 mmole),and Et₃N (0.071 mL, 0.51 mmole) were combined in CH₂Cl₂ (2 mL), and themixture was stirred overnight. MeOH (3 mL) and NaBH₄ (30 mg, 0.79 mmole)were added, and the reaction was stirred at room temperature for 2 hr.The solvent was removed in vacuo, and the residue was partitionedbetween H₂O and CHCl₃. The organic layer was washed with brine and dried(Na₂SO₄). The solvent was removed in vacuo, and the residue wasdissolved in a mixture of 1:2 MeOH/EtOAc (5 mL). A solution of HCl inEt₂O (1.0 M, 1.02 mL, 1.02 mmole) was added, and the precipitated solidwas collected, washed with EtOAc, and dried to afford the title compound(146 mg, 53%).

¹H NMR (400 MHz, CD₃OD) δ 9.06 (d, J=5.7 Hz, 1H), 8.33 (d, J=5.7 Hz,1H), 8.22 (d, J=9.9 Hz, 1H), 7.87 (s, 1H), 7.86(d, J=9.9 Hz, 1H), 7.59(d, J=7.6 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.43 (d, J=9.0 Hz, 1H), 4.35(s, 2H), 4.21 (s, 3H), 4.15 (m, 1H), 3.85 (m, 2H), 3.31–3.81 (m, 5H),3.16(m, 2H), 2.40–2.64 (m, 2H), 2.20–2.45 (m, 2H).

MS (ES) m/z 466.0 (M+H)⁺.

Example 367-Fluoro-6-{{1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-benzo[1,4]thiazin-3-one,monotrifluoroacetate

(a)1-tert-Butoxycarbonyl-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)amino]piperidine

To a stirred solution of aldehyde (22 g) (0.22 g, 1.05 mmole) in CH₂Cl₂(20 mL) and dry MeOH (5 mL) at RT under N₂ was added4-amino-1-(tert-butoxycarbonyl)piperidine (0.31 mg, 1.5 mmole). After 36h, the reaction mixture was concentrated. The remaining residue wasdissolved in dry isopropanol (20 mL) and reacted with NaBH₄ (0.08 mg,2.1 mmole). After 12 h at RT, the reaction was concentrated under vacuumand the residue was purified by flash chromatography on silica gel (5%MeOH/CH₂Cl₂) to afford a yellow solid (0.4 g, 97%).

MS (ES) m/z 396 (M+H)⁺.

(b) 7-Fluoro-6-(piperidin-4-ylaminomethyl)-4H-benzo[1,4]thiazin-3-one

The carbamate (36a) was treated with 6 N HCl at RT under N₂. After 30 h,1.0 N NaOH was added to the reaction until pH=7, and the solution wasconcentrated under vacuum. Flash chromatography on silica gel (20%MeOH/CH₂Cl₂) afforded an off-white solid (0.27 mg, 91%).

MS (ES) m/z 296 (M+H)⁺.

(c) Title Compound

To a stirred solution of amine (36b) (0.27 g, 0.9 mmole) in dry DMF atRT under N₂ was added the oxirane (1b) (0.2 g, 1.0 mmole). The solutionwas treated with lithium perchlorate (0.1 g, 0.9 mmole) addedportionwise at RT. The reaction mixture was stirred and heated at 80° C.for 36 hr, then was cooled to room temperature and concentrated undervacuum. The residue was purified by flash chromatography on silica gel(50:1 CH₂Cl₂/MeOH containing 2% NH₄OH). Further purification byreversed-phase preparative HPLC (gradient elution: 5 to 95% CH₃CN/H₂Ocontaining 0.1% TFA) gave the title compound (0.05 g, 12%).

MS (ES) m/z 497 (M+H)⁺

Example 376-{{1-[(R)-2-Hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one,hydrochloride

(R)-2-(4-Aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl)ethanol (1d)hydrochloride (189 mg, 0.56 mmole), aldehyde (30e) (100 mg, 0.56 mmole),and Et₃N (0.078 mL, 0.56 mmole) were combined in DMF (2 mL), and themixture was stirred overnight. MeOH (3 mL) and NaBH₄ (32 mg, 0.84 mmole)were added, and the reaction was stirred at room temperature for 30 min.6.0 N HCl (0.2 mL) was added, and the reaction was stirred for anadditional 5 min. The reaction was quenched with saturated NaHCO₃ (2mL), the solvent was removed in vacuo, and the residue was partitionedbetween H₂O and CHCl₃. The organic layer was washed with brine and dried(Na₂SO₄). The solvent was removed in vacuo, and the residue wasdissolved in a mixture of 1:3 MeOH/EtOAc (5 mL). A solution of HCl inEt₂O (1.0 M, 0.56 mL, 0.56 mmole) was added, and the precipitated solidwas collected, washed with EtOAc, and dried to afford the title compound(100 mg, 36%).

¹H NMR (400 MHz, CD₃OD) δ 9.05 (d, J=5.7 Hz, 1H), 8.31 (d, J=5.7 Hz,1H), 8.20 (d, J=9.9 Hz, 1H), 7.87 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39(d, J=8.0 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 6.44 (d, J=9.2 Hz, 1H), 4.70(s, 2H), 4.34 (s, 2H), 4.15 (s, 3H), 4.01 (m, 1H), 3.31–3.75 (m, 6H),2.40–2.54 (m, 2H), 2.20–2.45 (m, 2H).

MS (ES) m/z 464.0 (M+H)⁺.

Example 38(R)-2-{4-[(2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,dihydrochloride

(a) (2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl) methanol

A solution of methyl ester (20b) (1.0 g) in dry tetrahydrofuran (170 ml)was treated with a 1M solution of lithium aluminium hydride in ether (14ml) and the mixture was heated under reflux for 18 hours. It was cooledand a slight excess of 2N sodium hydroxide was added followed bychloroform and anhydrous sodium sulphate, and the mixture was stirredfor 30 minutes and filtered. The solution was evaporated to dryness togive an oil (0.70 g).

MS (APCI⁺) m/z 183 (MH⁺)

(b) 2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde

The alcohol (38a) (0.70 g) in dry tetrahydrofuran-chloroform (1:1) (50ml) was stirred with manganese dioxide (1.2 g) for 18 hours and themixture was filtered. The filtrate was evaporated and chomatographed onsilica gel, eluting with chloroform to afford a yellow solid (0.205 g).

MS (APCI⁺) m/z 181 (MH⁺)

(c) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl) ethanol (1d)hydrochloride salt (0.146 g, 0.43 mmole) in CH₂Cl₂ (3 mL) and drymethanol (2 mL) at RT was added triethylamine (60 uL, 0.52 mmole),aldehyde (38b) (0.065 g, 0.36 mmole), and granular Na₂SO₄ (approximately200 mg). After 12 h, the reaction was filtered through a sintered-glassfunnel and the filtrate was concentrated and azeotroped three times withacetonitrile. The remaining residue was dissolved in dry methanol andreacted with NaBH₄ (0.04 g, 1.0 mmole). After 12 h at RT, the mixturewas poured into saturated aqueous sodium bicarbonate solution (10 mL)and extracted with chloroform (3×10 mL). The combined organic phaseswere dried over Na₂SO₄, filtered, and concentrated. The residue wasdissolved in methanol (1 mL) and diluted with ethyl acetate (4 mL).While stirring a solution of 1.0 M HCl in ether (0.8 mL) was addeddropwise. The product was collected by suction filtration, washed withethyl acetate then Et₂O, and dried under vacuum to afford the titlecompound (0.145 g, 75%) as a tan solid.

MS (ES) m/z 466 (M+H)⁺.

Example 39(R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol,dihydrochloride

(R)-2-(4-Aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (186 mg, 0.61 mmole), aldehyde (35b) (92 mg, 0.51 mmole), andanhydrous Na₂SO₄ powder (a catalytic amount) were combined in CH₂Cl₂ (2mL), and the mixture was stirred overnight. MeOH (3 mL) and NaBH₄ (30mg, 0.79 mmole) were added, and the reaction was stirred at roomtemperature for 2 hr. The solvent was removed in vacuo, and the residuewas partitioned between H₂O and CHCl₃. The organic layer was washed withbrine and dried (Na₂SO₄). The solvent was removed in vacuo, and theresidue was dissolved in a mixture of 1:2 MeOH/EtOAc (5 mL). A solutionof HCl in Et₂O (1.0 M, 1.02 mL, 1.02 mmole) was added, and theprecipitated solid was collected, washed with EtOAc, and dried to affordthe title compound (135 mg, 49%).

¹H NMR (400 MHz, CD₃OD) δ 9.10 (d, J=5.6 Hz, 1H), 8.47 (d, J=9.3 Hz,1H), 8.48 (d, J=5.6 Hz, 1H), 7.68 (d, J=9.6 Hz, 1H), 7.62 (d, J=9.3 Hz,1H), 6.94 (d, J=7.7 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 4.38 (s, 2H), 4.25(s, 3H), 4.15 (m, 1H), 3.71–3.91 (m, 5H), 3.31–3.52 (m, 3H), 3.30 (s,1H), 2.40–2.54 (m, 2H), 2.20–2.45 (m, 2H).

MS (ES) m/z 467.0 (M+H)⁺.

Example 40(R)-2-{4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxyquinolin-4-yl)ethanol

(a) 5-Bromo-pyridine-2,3-diol

This compound was made according to the procedure of Dallacker, F;Fechter, P; Mues, V Journal Z. Naturforsch, 1979, 34b, 1729–1736 from2-furaldehyde.

MS (APCI+) m/z 190/192 (M+).

(b) 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

The diol (40a) (34 g) in DMF (400 ml) and potassium carbonate (51 g) wastreated with 1,2-dibromoethane (16 mL) and the mixture was heated at 85°C. overnight and evaporated. The residue was treated with sodiumhydroxide, extracted with ethyl acetate and chromatographed on silicagel, eluting with methanol-dichloromethane (1:50) to afford a paleyellow solid (4.92 g; 13%)

MS (APCI+) m/z 216/218 (MH+).

(c) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic acid butylester

Bromide (40b) (1.14 g) was slurried in butanol at room temperature anddegassed with a stream of carbon monoxide gas for 10 minutes.1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL, 3.38 mmol), palladiumdichloride (30 mg, 0.169 mmol) and 1,3-bis(diphenylphosphino)propane(139 mg, 0.338 mmol) was added. The mixture was heated to 100° C. underan atmosphere of carbon monoxide for 12 hours. The volatiles were thenremoved under reduced pressure and the residue partitioned between ethylacetate (2×100 mL) and water (20 mL). The organic phases were combinedand dried over magnesium sulfate. The solvent was once again removed invacuo and the residue subjected to purification on silica gel employingan ethyl acetate and hexane solvent gradient. This provided the desiredproduct as a colourless oil (0.436 g, 54%).

MS (APCI+) m/z 238 (MH+).

(d) (2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-methanol

Ester (40c) was dissolved in tetrahydrofuran (10 mL). The solution wascooled to 0° C. and a solution of lithium aluminium hydride intetrahydrofuran (1M, 3.68 mL, 3.68 mmol) was added dropwise. Thereaction was stirred at 0° C. for 1 hour and then quenched by theaddition of water (2 mL). The volatiles were removed in vacuo and theresidue partitioned between ethyl acetate (3×100 mL) and water (20 mL).The organic phases were combined and concentrated to provide the desiredcompound which was used without further purification (320 mg).

MS (APCI+) mkz 168 (MH+).

(e) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxaldehyde

The alcohol (40d) (0.67 g) in dichloromethane (20 mL) was stirredovernight with manganese dioxide (1.5 g), filtered, evaporated andchromatographed on silica gel, eluting with methanol-dichloromethane(1:50) to give a colourless oil (0.49 g, 74%).

MS (APCI+) m/z 166 (MH+).

(f) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl) ethanol (1d)mono hydrochloride salt (0.18 g, 0.55 mmole) in CH₂Cl₂ (25 mL) and dryethanol (10 mL) at RT was added the aldehyde (40e) (0.09 g, 0.55 mmole),triethylamine (0.08 mL, 0.60 mmole), and granular Na₂SO₄ (approximately100 mg). After 36 h, the reaction was filtered through a sintered-glassfunnel and the filtrate was concentrated. The remaining residue wasdissolved in dry ethanol and reacted with NaBH₄ (0.02 g, 0.55 mmole).After 12 h at RT, the reaction was concentrated under vacuum and theresidue was dissolved in a mixture of H₂O (2 mL) and saturated aqueousNaHCO₃ (10 mL). The aqueous solution was extracted with EtOAc (2×50 mL)and the combined organic phases were washed with brine then were driedover Na₂SO₄. Flash chromatography on silica gel (9:1 CHCl₃/MeOHcontaining 5% NH₄OH) afforded the title compound (0.17 g, 69%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=4.5 Hz, 1H), 8.04 (d, J=9.8 Hz,1H), 7.73 (d, J=2.0 Hz, 1H), 7.63 (d, J=4.5 Hz, 1H), 7.35 (m, 1H), 7.25(d, J=2.0 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 5.42 (m, 1H), 4.41 (m, 2H),4.23 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H), 3.25 (m, 1H), 2.83 (m, 2H),2.57 (m, 2H), 2.37 (app t, J=9.8 Hz, 1H), 2.20 (app t, J=9.8 Hz, 1H),1.96 (m, 2H), 1.49 (m, 2H).

MS (ES) m/z 451 (M+H)⁺.

The following Examples 100–108 were prepared from the correspondingcarboxaldehyde, which were prepared from commercially available startingmaterials by standard methods, by analogous methods to Example 1.Example 109 was prepared from Example 18 by hydrogenation over Pd oncarbon.

R⁴ = —U—R⁵ Example salt U R⁵ 100 AY CH₂ 6-benzooxazin-3-one-2,2-Me

101 AY CH₂ 6-benzooxazin-3-one-4-Me

102 AY CH₂ 6-benzothiazol-2-one-3-Me

103 AY CH₂ 6-dioxobenzothiazin-3-one

104 AY CH₂ 7-benzooxazin-3-one-4-Me

105 AY CH₂ 7-(3,4-dihydro-1H-quinolin-2-one)

106 AY CH₂ 6-(7,8-difluoro-4H-benzo[1,4]thiazin-3-one)

107 AY CH₂ 7-[4-methyl-3,4-dihydro-1H-quinoxalin-2-one]

108 AY CH₂ 2-[6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one]

109 AY CH₂ 5-[6-amino-benzo[1,3]dioxole]

R⁴ = —U—R⁵ Example salt R¹ X U R⁵ 110 M 3-CO₂Et (mixture ofisomers) CHCH₂ 6-benzothiazin-3-one

111 AY 4-CO₂CH₂CH═CH₂ N CH₂ 6-benzothiazin-3-one

112 B 4-CO₂H N CH₂ 6-benzothiazin-3-one

Example 110 was prepared from4-amino-1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidine-3-carboxylicacid ethyl ester (Example 2(e) of WO01/07433) by the method of Example16. Example 111 was prepared from 4-amino-piperidine-1,4-dicarboxylicacid mono-tert-butyl ester (comercially available) by reaction withaldehyde (6c) and triacetoxyborohydride, allylbromide/triethylamine/DMF, de-protection with trifluoroacetic acid andfinally reaction with oxirane (2e) in acetonitrile and lithiumperchlorate. Example 112 was prepared from Example 111 by reaction withPd(Ph₃P)₄ and Bu₃SnH in THF.

Example 1136-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one

(a) 2-Amino-3-(hydroxymethyl)pyridine

Solid 2-aminonicotinic acid (199 g, 1.44 mole) was added in portionsover 4 hr to 1.0 M LiAlH₄ in THF (3 L, 3 mole) with stirring underArgon. An ice-bath was applied to control the temperature below 30° C.After the addition was complete, the reaction was heated at reflux for16 hr, then was cooled to 0° C. and carefully quenched by sequentialaddition of H₂O (120 mL), 15% NaOH in H₂O (120 mL), and H₂O (350 mL).The resulting thick suspension was stirred for 1 hr, then was filteredthrough a pad of celite®. The filter pad was rinsed with THF (1 L), andthe filtrate was concentrated to dryness to give the title compound (156g, 87%) as a pale yellow waxy solid: MS (ES) m/e 125.1 (M+H)⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 7.84 (dd, 1H), 7.37 (m, 1H), 6.53 (dd, 1H), 5.65(br s, 2H), 5.16(t, 1H), 4.34 (d, J=4.6 Hz, 2H).

(b) 2-Amino-5-bromo-3-(hydroxymethyl)pyridine hydrobromide

To a stirred solution of 2-amino-3-(hydroxymethyl)pyridine (113a) (156g, 1.257 mole) in HOAc (2.5 L) at ambient temperature was added bromine(64.1 mL, 1.257 mole) dropwise over 1 hr. A suspension began to formduring the addition. An exotherm to 36° C. was controlled with an icebath. After the addition, the reaction mixture was stirred at ambienttemperature overnight. The yellow precipitate was filtered, washed withether and air-dried to give the title compound (289 g, 81%): MS (ES) m/e203.2 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆, free base) δ 7.89 (d, J=2.3 Hz,1H), 7.52 (s, 1H), 5.92 (br s, 2H), 5.29 (br s, 1H), 4.30 (s, 2H).

(c) 2-Amino-5-bromo-3-(bromomethyl)pyridine hydrobromide

A suspension of 2-amino-5-bromo-3-(hydroxymethyl)pyridine hydrobromide(113b) (289 g, 1.02 mole) in 48% aqueous HBr (2.9 L) was heated atreflux for 12 hrs. Complete solution occurred during heating. Thereaction mixture was cooled and a crystalline precipitate formed. Thiswas filtered and washed with ethyl acetate and air dried to give thetitle compound (305 g, 86%).

(d) Methyl(±)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-[1,8]naphthyridine-3-carboxylate

To a solution of dimethyl malonate (224 g, 1.7 mole) in DMF (2 L) andTHF (2 L) stirred under argon and chilled to 3° C. with an ice-acetonebath was added NaH (60% Nujol dispersion, 69.2 g, 1.7 mole) in portionsover 1.5 hr. The anion solution was stirred for 15 min at ca. 5° C.,then 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (113c) (200 g,0.56 mole) was added in portions over 15 min. The reaction mixture wasallowed to warm to ambient temperature during overnight stirring andthen was heated to 80° C. for 2 hr. The reaction was then cooled andfiltered and the precipitate was washed with ethyl acetate. This solidwas then vigorously stirred in 2 L water for 15 min and again filteredand air-dried to give the title compound (113 g, 71%): MS (ES) m/e 286(M+H)⁺.

(e) 6-Bromo-3,4-dihydro-1H-1H-[1,8]naphthyridin-2-one

To a suspension of methyl(±)-6-bromo-2-oxo-1,2,3,4-tetrahydro-1H-[1,8]naphthyridine-3-carboxylate(113d) (170 g, 0.596 mole) in CH₃OH (10 L) was added 1.0 M NaOH (2.5 L).The reaction mixture was stirred and heated at reflux for 5 hrs and thencooled to ambient temperature. The suspension was acidified with 1.0 MHCl (3.0 L) and then was stirred and heated at reflux overnight. Thereaction slurry was cooled and filtered and the solid was washed withwater and vacuum dried to give the title compound (122 g of the hydrate,90%) as an off-white solid, HPLC purity, 94%: MS (ES) m/e 228 (M+H)⁺.

(f) 6-Vinyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

6-Bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one (113e) (4.6 g, 20.3mmole) and tributyl(vinyl)tin (7.7 g, 24.4 mmole) were dissolved in DMF(200 mL) and the solution was degassed with nitrogen. (Ph₃P)₄Pd (590 mg,0.5 mmole) was added to the solution. The reaction was heated to 105° C.under nitrogen overnight, then was cooled to room temperature andfiltered through a sintered glass funnel. The filtrate was washed withNH₄OH and extracted with EtOAc (2×150 mL). The combined organic phaseswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo toafford the title compound (2.1 g, 60%) as an off white solid: MS (ES)m/e 175 (M+H)⁺.

(g) 7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxaldehyde

6-Vinyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (113f) (0.46 g, 2.6mmole) was dissolved in CH₂Cl₂ (50 mL) and the solution was cooled to−78° C. Ozone was bubbled through the solution with stirring until apale blue color-appeared, then the excess ozone was removed by bubblingoxygen through the solution for 15 min. Dimethylsulfide (0.30 mL, 4.8mmole) was added and the reaction was stirred at −78° C. for 3 hr, thenwas allowed to warm to RT overnight. The solvent was removed in vacuo.Flash chromatography on silica gel (9:1 CHCl₃/MeOH containing 5% NH₄OH)afforded the title compound (0.21 g, 45%) as an off white solid: MS (ES)m/e 177 (M+H)⁺.

(h) Title Compound

To a stirred solution of(R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol(2f) (0.34 g, 1.13 mmole) in dichloroethane (10 mL) and dry ethanol (5mL) at RT was added7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxaldehyde (113 g)(0.20 g, 1.13 mmole) and granular Na₂SO₄ (approximately 100 mg). After72 h, the reaction was concentrated. The remaining residue was dissolvedin dry ethanol and reacted with NaBH₄ (0.043 g, 1.13 mmole). After 12 hat RT, the reaction was concentrated under vacuum and the residue wasdissolved in a mixture of H₂O (10 mL) and saturated aqueous NaHCO₃ (50mL). The aqueous solution was extracted with EtOAc (2×75 mL) and thecombined organic phases were washed with brine then were dried overNa₂SO₄. Flash chromatography on silica gel (9:1 CHCl₃/MeOH containing 5%NH₄OH) afforded the title compound (0.11 g, 21%) as a white solid: ¹HNMR (400 MHz, d₆-DMSO) δ 10.43 (br s, 1H), 8.77 (d, J=4.5 Hz, 1H), 8.23(d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.75 (d, J=4.5 Hz, 1H), 7.58 (s, 1H),7.24 (d, J=9.0 Hz, 1H), 5.77 (m, 1H), 5.23 (br s, 1H), 4.02 (s, 3H),3.63 (s, 2H), 3.38 (m, 2H), 3.11 (m, 1H), 2.83 (m, 2H), 2.65 (m, 1H),2.47 (m, 2H), 2.32 (m, 1H), 2.17 (m, 1H), 1.79 (m, 2H), 1.27 (m, 2H); MS(ES) m/e 463 M+H)⁺.

The following Examples 150 and 151 were prepared by analogous methods toExample 7, using the carboxaldehydes 5b and 14a.

Example 180 was prepared from 6-trifluoromethoxy-quinolin-4-ylamine(prepared from 4-trifluoromethoxyaniline by addition to methylpropiolate, cyclisation in refluxing Dowtherm, reaction withtrifluoromethane sulfonic anhydride and heating with n-propylamine) bythe method of Example 7b-d. Example 181 was prepared from aldehyde 14aand [3-(4-amino-quinolin-6-yloxy)-propyl]-carbamic acid benzyl ester(prepared from Example (1a) by cleavage of the methyl ether to thecorresponding phenol with concentrated hydrobromic acid, esterificationusing concentrated hydrochloric acid/methanol, alkylation of the phenolwith (3-bromo-propyl)-carbamic acid benzyl ester using potassiumcarbonate in N,N-dimethylformamide, hydrolysis of the methyl ester tothe corresponding acid with aqueous sodium hydroxide, Curtiusrearrangement of the acid with diphenylphosphoryl azide in tert-butanolto give [6-(3-benzyloxycarbonylamino-propoxy)-quinolin-4-yl]-carbamicacid tert-butyl ester then standard treatment with trifluoroacetic acid)by the method of Example 7b-d followed by hydrogenation.

R⁴ = —U—R⁵ Example salt U R⁵ 150 G CH₂ 6-benzooxazin-3-one

151 G CH₂ 6-benzooxazol-2-one-3-Me

R⁴ = —U—R⁵ Ex- ample salt R¹ U R⁵ 180 G CF₃ CH₂ 6-benzothiazin-3-one

181 G H₂NCH₂CH₂CH₂ CH2 6-benzooxazol-2-one-3-Me

Example 186 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicAcid{1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl}amidedihydrochloride

Free base of the title compound was prepared by the method of Example189 using4-amino-1-[(R)-2-hydroxy-2-(6-methoxyquiolin-4-yl)ethyl]piperidine (1d)(34%). 1H NMR (CDCL₃) δ 1.45–1.6 (1H, m), 1.6–1.75 (1H, m), 2.01 (2H,broad d), t), 2.52 (1H, t), 2.60 (1H, dd), 2.85–2.95 (2H, m), 3.31 (1H,broad d), 3.56 (2H, s), 3.94 (3H, s), 3.9–4.05 (1H, m), 5.46 (1H, dd),7.19 (1H, d), 7.3–7.4 (2H, m), 7.7–7.8 (2H, m), 7.82 (1H, d), 8.15 (1H,d), 8.83 (1H, d), 9.57 (1H, broad s)

Free base was converted into dihydrochloride by the method of Example189.

MS (−ve ion electrospray) m/z 492 ([M−H]⁻, 100%)

Example 1877-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl}amidedihydrochloride

Free base of the title compound was prepared by the method of Example189 using4-amino-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidine (1d)and 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid (33c) (32%). 1H NMR (CDCL₃) δ 1.25–1.5 (1H, m), 1.5–1.8 (1H, m),1.85–2.05 (2H, m), 2.31 (1H, t), 2.47 (1H, t), 2.59 (1H, dd), 2.86 (2H,broad d), 3.28 (1H, broad d), 3.56 (2H, s), 3.8–4.0 (4H, m), 5.46 (1H,dd), 7.18 (1H, d), 7.29 (1H, d), 7.39 (1H, dd), 7.74 (1H, d), 7.91 (1H,s), 8.16 (1H, d), 8.82 (1H d),

MS (−ve ion electrospray) m/z 570 and 572 ([M−H]⁻, 100%)

Free base was converted into dihydrochloride by the method of Example189.

Example 1887-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[(R)-2-hydroxy-2-(6-methoxy[1,5]naphthyridin-4-yl)ethyl]piperidin-4-yl}amidedihydrochloride

Free base of the title compound was prepared by the method of Example189 using4-amino-1-[(R)-2-hydroxy-2-(6-methoxy[1,5]naphthyridin-4-yl)ethyl]piperidine(2f) and7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid (33c) (27%).

1H NMR (CDCL₃) δ 1.4–1.8 (2H, m), 2.0–2.2 (2H, m), 2.32 (1H, dt),2.4–2.6 (2H, m), 2.87 (1H, broad d), 3.11 (1H, dd), 3.34 (1H, broad d),3.56 (2H, s), 3.8–4.1 (4H, m), 5.75 (1H, dd), 7.13 (1H, d), 7.27 (1H,d), 7.83 (1H, d), 7.95 (1H, s), 8.26 (1H, d), 8.81 (1H, d).

MS (−ve ion electrospray) m/z 571 and 573 ([M−H]⁻, 100%)

Free base was converted into dihydrochloride by the method of Example189.

Example 189 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[(R)-2-hydroxy-2-(6-methoxy[1,5]naphthyridin-4-yl)ethyl]piperidin-4-yl}amidedihydrochloride

A solution of(R)-1-[2-hydroxy-2-(6-methoxy[1,5]naphthyridin-4-yl)]ethyl-4-aminopiperidine(Example 2f) (100 mg),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (31b)(70 mg) and pyridine (0.027 ml) in dichloromethane (2 ml)/DMF (2 ml) wasice-cooled and treated with dicyclohexylcarbodiimide (206 mg). Afterwarming to room temp. over 1 hour the mixture was stirred 18 hours,diluted with chloroform (20 ml), washed with saturated aqueous sodiumbicarbonate, dried and evaporated to dryness. Chromatography, elutingwith chloroform/methanol/0.88 aqueous ammonia 19:1:0.1, gave free baseof the title compound (129 mg).

1H NMR (CDCl₃) δ1.5–1.9 (2H, m), 2.0–2.1 (2H, m), 2.33 (1H, dt), 2.4–2.6(2H, m), 2.87 (1H, d), 3.11 (1H, dd), 3.34 (1H, d), 3.55 (2H, s),3.95–4.05 (1H, m), 4.05 (3H, s), 5.75 (1H, dd), 7.13 (1H, d), 7.42 (1H,d), 7.77 (1H, d), 7.84–7.86 (2H, m), 8.26 (1H d), 8.70 (1H, broad s),8.81 (1H, d).

A chloroform solution of this material was treated with 1M HCl in ether(0.65 ml) and evaporated to dryness to give title compound (115 mg).

MS (−ve ion electrospray) m/z 493 ([M−H]⁻, 100%)

The following Example 190 was prepared from5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid by themethod of Example 12b. Examples 191 and 192 were prepared by analogousmethods from the acids 6a and 2,2-difluorobenzo[1,3]dioxole-5-carboxylicacid. Examples 200–204 were prepared by analogous methods to Example 15,but Example 204 used amine Example 2f.

R⁴ = —U—R⁵ Example salt X U R⁵ 190 DZ CH CO 4-thiazolopyrimidin-5-one

191 G CH CO 6-benzothiazin-3-one

192 CH CO 5-(2,2-Difluoro-benzo[1,3]dioxole)

200 G CH SO₂ 6-benzodioxine

201 G CH SO₂ 6-benzooxazin-3-one

202 G CH SO₂ 6-(7-chloro-benzothiazin-3-one)

203 G CH SO₂ 7-benzothiazepin-4-one

204 N SO₂ 6-benzothiazin-3-one

Key to salts

-   AY dioxalate-   G oxalate-   DZ mesylate-   M trifluoroacetate-   B dihydrochloride    Biological Activity

The MIC (μg/ml) of test compounds against various organisms wasdetermined: S. aureus Oxford, S. aureus WCUH29, S. pneumoniae 1629, S.pneumoniae N1387, S. pneumoniae ERY 2, H. influenzae Q1, E.faecalis 1.

Examples 1–4, 6–10, 16, 18, 19, 22–40, 186–189 have an MIC of less thanor equal to 0.125 μg/ml; 5, 11–15, 17, 20, 21, 101, 102, 105, 106,109–110, 191, 192, 203, 204 have an MIC of less than or equal to 2μg/ml; 100, 103, 104, 107, 111–113, 150, 190, 200–202 have an MIC lessthan or equal to 32 μg/ml against one or more of the above range of grampositive and gram negative bacteria.

1. A compound of formula (I) or a pharmaceutically acceptable saltand/or N-oxide thereof:

wherein: one of Z¹, Z², Z³, Z⁴ and Z⁵ is N, one is CR^(1a) and theremainder are CH , or one of Z¹, Z², Z³, Z⁴ and Z⁵ is CR^(1a) and theremainder are CH; R¹ and R^(1a) are independently hydrogen; hydroxy;(C₁₋₆)alkoxy optionally substituted by (C₁₋₆)alkoxy, amino, piperidyl,guanidino or amidino any of which is optionally N-substituted by one ortwo (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups, CONH₂, hydroxy,(C₁₋₆)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy,acylthio, acyloxy or (C₁₋₆)alkylsulphonyloxy;(C₁₋₆)alkoxy-substituted(C₁₋₆) alkyl; halogen; (C₁₋₆)alkyl;(C₁₋₆)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl;acyloxy; acylthio; (C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide;arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino oramidino group optionally N-substituted by one or two (C₁₋₆)alkyl, acylor (C₁₋₆)alkylsulphonyl groups; or when Z⁵ is CR^(1a), R^(1a) mayinstead be cyano, hydroxymethyl or carboxy; provided that when none ofZ¹, Z², Z³, Z⁴ and Z⁵ is N, then R¹ is not hydrogen; R² is hydrogen, or(C₁₋₄)alkyl or (C₂₋₄)alkenyl optionally substituted with 1 to 3 groupsselected from: amino optionally substituted by one or two (C₁₋₄)alkylgroups; carboxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; aminocarbonyl whereinthe amino group is optionally substituted by hydroxy, (C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₄)alkenylsulphonyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl or(C₂₋₄)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionallysubstituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;1,2,4-triazol-5-yl optionally substituted by R¹⁰;5-oxo-1,2,4-oxadiazol-3-yl; halogen; (C₁₋₄)alkylthio; trifluoromethyl;hydroxy optionally substituted by (C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl;(C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; R³ ishydrogen; or R³ is in the 2-, 3- or 4-position and is: carboxy;(C₁₋₆)alkoxycarbonyl; (C₂₋₆)alkenyloxycarbonyl aminocarbonyl wherein theamino group is optionally substituted by hydroxy, (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; cyano;tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted byR¹⁰; 5-oxo-1,2,4-oxadiazol-3-yl; or (C₁₋₄)alkyl or ethenyl optionallysubstituted with any of the substituents listed above for R³ and/or 0 to2 groups R¹² independently selected from: halogen; (C₁₋₆)alkylthio;trifluoromethyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy optionallysubstituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylcarbonyl or(C₂₋₆)alkenylcarbonyl; amino optionally mono- or disubstituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,(C₂₋₆)alkenylsulphonyl or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; oxo;(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or when R³ is in the 3-position, hydroxy optionallysubstituted as described above; in addition when R³ is disubstitutedwith a hydroxy or amino containing substituent and carboxy containingsubstituent these may together form a cyclic ester or amide linkage,respectively; R⁴ is a group —U—R⁵ where U is selected from CO, SO₂ andCH₂ and R⁵ is an optionally substituted bicyclic carbocyclic orheterocyclic ring system (A):

containing up to four heteroatoms in each ring in which ring (a) isaromatic and ring (b) is non-aromatic; X¹ is C or N; X² is N, NR¹³, O,S(O)_(x), CO or CR¹⁴; X³ and X⁵ are independently N or C; Y¹ is a 0 to 4atom linker group each atom of which is independently selected from N,NR¹³, O, S(O)_(x), CO and CR¹⁴; Y² is a 2 to 6 atom linker group, eachatom of Y² being independently selected from N, NR¹³, O, S(O)_(x), CO,CR¹⁴ and CR¹⁴R¹⁵; each of R¹⁴ and R¹⁵ is independently selected from: H;(C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy;halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl;formyl; (C₁₋₄)alkylcarbonyl; (C₂₋₄)alkenyloxycarbonyl(C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally mono- or di-substituted by(C₁₋₄)alkyl or (C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl; aryl(C₁₋₄)alkoxy;each R¹³ is independently H; trifluoromethyl; (C₁₋₄)alkyl optionallysubstituted by hydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo ortrifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl; arylcarbonyl;heteroarylcarbonyl; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl;(C₁₋₆)alkylsulphonyl; or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,(C₂₋₄)alkenyloxycarbonyl, (C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or(C₂₋₄)alkenyl and optionally further substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; each x is independently 0, 1 or 2 n is 0 and AB is NR¹¹CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NHR¹¹SO₂, CR⁶R⁷—SO₂ or CR⁶R⁷—CR⁸R⁹; or n is 1and AB is NR¹¹CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NR¹¹SO₂, CONR¹¹, CR⁶R⁷—CR⁸R⁹,O—CR⁸R⁹ or NR¹¹—CR⁸R⁹; wherein CR⁶R⁷ is CH₂, CHOH, CH(NH₂), C(Me)(OH) orCH(Me) and CR⁸R⁹ is CH₂; R¹⁰ is selected from (C₁₋₄)alkyl; (C₂₋₄)alkenyland aryl any of which may be optionally substituted by a group R¹² asdefined above; carboxy; aminocarbonyl wherein the amino group isoptionally substituted by hydroxy, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkylor (C₂₋₆)alkenyl; and R¹¹ is hydrogen; trifluoromethyl, (C₁₋₆)alkyl;(C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionallyfurther substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or where one of R³and R⁶ or R⁷ contains a carboxy group and the other contains a hydroxyor amino group they may together form a cyclic ester or amide linkage.2. A compound according to claim 1 wherein Z⁵ is CH or N, Z³ is CH or CFand Z¹, Z² and Z⁴ are each CH, or Z¹ is N, Z³ is CH or CF and Z², Z⁴ andZ⁵ are each CH.
 3. A compound according to claim 1 wherein R¹ is methoxyand R^(1a) is H or when Z³ is CR^(1a) it may be C—F.
 4. A compoundaccording to claim 1 wherein R³ is hydrogen; optionally substitutedhydroxy; (C₁₋₄)alkoxycarbonyl; CONH₂; 1-hydroxyalkyl; CH₂CO₂H; CH₂CONH₂;—CONHCH₂CONH₂; 1,2-dihydroxyalkyl; CH₂CN; 2-oxo-oxazolidin-5-yl or2-oxo-oxazolidin-5-yl(C₁₋₄alkyl).
 5. A compound according claim 1wherein n is 0 and either A is CHOH and B is CH₂ or A is NH and B is CO.6. A compound according to claim 1 wherein —U— is —CH₂—.
 7. A compoundaccording to claim 1 wherein in the heterocyclic ring (A) Y² has 3–5atoms including (a) NR¹³, O or S bonded to X⁵ and NHCO bonded via N toX³, or (b) O or NH bonded to X³.
 8. A compound according to claim 1wherein R⁵ is selected from: 2,3-dihydro-benzo[1,4]dioxin-6-ylbenzo[1,3]dioxol-5-yl 2,2-difluoro-benzo[1,3]dioxol-5-yl4H-benzo[1,4]oxazin-3-one-6-yl 4H-benzo[1,4]thiazin-3-one-6-yl7-fluoro-4H-benzo[1,4]oxazin-3-one-6-yl 6-chloro-benzo[1,3]dioxol-5-yl5-fluoro-3-methyl-3H-benzooxazol-2-one-6-yl(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl and7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.
 9. Acompound according to claim 1 selected from:(R)-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,(R)-2-{4-[(2,3-Dihydro-benxo[1,4]dioxin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol,(R)-2-{4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-one,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one,7-Fluoro-6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]oxazin-3-one,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}methyl)-4H-benzo[1,4]oxazin-3-one,(R)-2-{4-[(6-Chloro-benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,5-Fluoro-6-({1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-3-methyl-3H-benzoxazol-2-one,2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid{1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-amide,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-3-methyl-3H-benzoxazole-2-thione,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-3-methyl-3H-benzoxazol-2-one,3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid{1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-yl}-amide,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one,4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-sulfonic acid{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-piperidin-4-yl}-amide,(R)-1-(6-Methoxy-quinolin-4-yl)-2-{4-[(6-nitro-benzo[1,3]dioxol-5-ylmethyl)-amino]-piperidin-1-yl}-ethanol,(R)-2-{4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,7-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-1-H-pyrido[2,3-b][1,4]thiazin-2-one,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}-methyl)-2-(R/S)-methyl-4H-benzo[1,4]thiazin-3-one,7-Fluoro-6-{{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-benzo[1,4]thiazin-3-one,(R)-2-{4-[(7-Fluoro-2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol,(R)-2-{4-(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol,(R)-1-(6-Methoxy-[1,5]naphthyridin-4-yl)-2-{4-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethanol,(R)-1-(6-Methoxyquinolin-4-yl)-2-{4-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethanol,6-[({(3S,4S)-3-Hydroxy-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)-4H-benzo[1,4]thiazin-3-one,6-[({(3R,4R)-3-Hydroxy-1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)-ethyl]piperidin-4-ylamino}methyl)-4H-benzo[1,4]thiazin-3-one,7-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-1H-pyrido[2,3-b][1,4]thiazin-2-one,7-{{1-[(R)-2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-4-ylamino}methyl}-2,3-dihydro-5H-benzo[b][1,4]thiazepine-4-one,6-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one,6-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]thiazin-3-one,(R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b[1,4]oxazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol,7-Bromo-6-{{1-[(R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b[1,4]thiazin-3-one,7-{{1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl}-1H-pyrido[3,4-b][1,4]thiazin-2-one,(R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,7-Fluoro-6-{{1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-benzo[1,4]thiazin-3-one,6-{{1-[(R)-2-Hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-ylamino}methyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one,(R)-2-{4-[(2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-quinolin-4-yl)-ethanol,(R)-2-{4-[(3,4-Dihydro-2H-pyrido[3,2-b](1,4]thiazin-6-ylmethyl)-amino]-piperidin-1-yl}-1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol,(R)-2-{4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)amino]piperidin-1-yl}-1-(6-methoxyquinolin-4-yl)ethanol,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid{1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl}amide,7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[(R)-2-hydroxy-2-(6-methoxyquinolin-4-yl)ethyl]piperidin-4-yl}amide,7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid{1-[(R)-2-hydroxy-2-(6-methoxy[1,5]naphthyridin-4-yl)ethyl]piperidin-4-yl}amide,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid{1-[(R)-2-hydroxy-2-(6-methoxy(1,5]naphthyridin-4-yl)ethyl]piperidin-4-yl}amide,6-({1-[(R)-2-Hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]piperidin-4-ylamino}methyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,the following compounds (a)-(j) of formula (1):

wherein R⁴=-U-R⁵: U R⁵ (a) CH₂ 6-benzooxazin-3-one-2,2-Me

(b) CH₂ 6-benzooxazin-3-one-4-Me

(c) CH₂ 6-benzothiazol-2-one-3-Me

(d) CH₂ 6-dioxobenzothiazin-3-one

(e) CH₂ 7-benzooxazin-3-one-4-Me

(f) CH₂ 7-(3,4-dihydro-1H-quinolin-2-one)

(g) CH₂ 6-(7,8-difluoro-4H-benzo[1,4]thiazin-3-one)

(h) CH₂ 7-[4-methyl-3,4-dihydro-1H-quinoxalin-2-one]

(i) CH₂ 2-[6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one]

(j) CH₂ 5-[6-amino-benzo[1,3]dioxide]

the following compounds (a)-(c) of formula (2):

wherein R⁴=-U-R⁵: R¹ X U R⁵ (a) 3-CO₂Et CH CH₂ 6-benzothiazin-3-one(mixture of isomers)

(b) 4- N CH₂ 6-benzothiazin-3-one CO₂CH₂CH═CH₂

(c) 4-CO₂H N CH₂ 6-benzothiazin-3-one

the following compounds (a)-(b) of formula (3):

wherein R⁴=-U-R⁵: U R⁵ (a) CH₂ 6-benzooxazin-3-one

(b) CH₂ 6-benzooxazol-2-one-3-Me

the following compounds (a)-(b) of formula (4):

wherein R⁴=-U-R⁵: R¹ U R⁵ (a) CF₃ CH₂ 6-benzothiazin-3-one

(b) H₂NCH₂CH₂CH₂ CH₂ 6-benzooxazol-2-one-3-Me

and the following compounds (a)-(h) of formula (5):

wherein R⁴=-U-R⁵: X U R⁵ (a) CH CO 4-thiazolopyrimidin-5-one

(b) CH CO 6-benzothiazin-3-one

(c) CH CO 5-(2,2-Difluoro-benzo[1,3]dioxole)

(d) CH SO₂ 6-benzodioxine

(e) CH SO₂ 6-benzooxazin-3-one

(f) CH SO₂ 6-(7-chlorobenzothiazin-3-one)

(g) CH SO₂ 7-benzothiazepin-4-one

(h) N SO₂ 6-benzothiazin-3-one

or a pharmaceutically acceptable salt and/or N-oxide thereof.
 10. Amethod of treatment of bacterial infections in mammals, particularly inman, which method comprises the administration to a mammal in need ofsuch treatment an effective amount of a compound according to claim 1.11. A pharmaceutical composition comprising a compound according toclaim 1, and a pharmaceutically acceptable carrier.
 12. A process forpreparing a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt and/or N-oxide thereof, which processcomprises reacting a compound of formula (IV) with a compound of formula(V):

wherein n is as defined in formula (I); Z^(1′), Z^(2′), Z^(3′), Z^(4′),Z^(5′), R^(1′), and R^(3′) are Z¹, Z², Z³, Z⁴, Z⁵, R¹, and R³ as definedin formula (I) or groups convertible thereto; Q¹ is NR^(2′)R^(4′) or agroup convertible thereto wherein R^(2′) and R^(4′) are R² and R⁴ asdefined in formula (I) or groups convertible thereto and Q² is H orR^(3′) or Q¹ and Q² together form an optionally protected oxo group; (i)X is A′-COW, Y is H and n is 0; (ii) X is CR⁶═CR⁸R⁹, Y is H and n is 0;(iii) X is oxirane, Y is H and n is 0; (iv) X is N═C═O and Y is H and nis 0; (v) one of X and Y is CO₂R^(Y) and the other is CH₂CO₂R^(X); (vi)X is CHR⁶R⁷ and Y is C(═O)R⁹; (vii) X is CR⁷═PR^(Z) ³ and Y is C(═O)R⁹and n=1; (viii) X is C(═O)R⁷ and Y is CR⁹═PR^(Z) ³ and n=1; (ix) Y isCOW and X is NHR^(11′) or NR11′COW and n=0 or 1 or when n=1 X is COW andY is NHR^(11′) or NR11′COW; (x) X is NHR^(11′) and Y is C(═O)R⁸ and n=1;(xi) X is NHR^(11′) and Y is CR⁸R⁹W and n=1; (xii) X is NR^(11′) COCH₂Wor NR^(11′)SO₂CH₂W and Y is H and n=0; (xiii) X is CR⁶R⁷SO₂W and Y is Hand n=0; (xiv) X is W or OH and Y is CH₂OH and n is 1; (xv) X isNHR^(11′) and Y is SO₂W or X is NR^(11′)SO₂W and Y is H, and n is 0;(xvi) X is W and Y is CONHR^(11′); in which W is a leaving group; R^(X)and R^(Y) are (C₁₋₆)alkyl; R^(Z) is aryl or (C₁₋₆)alkyl; A′ and NR^(11′)are A and NR¹¹ as defined in formula (I), or groups convertible thereto;and oxirane is:

wherein R⁶, R⁸ and R⁹ are as defined in formula (I); and thereafteroptionally or as necessary converting Q¹ and Q² to NR^(2′)R^(4′);converting A′, Z^(1′), Z^(2′), Z^(3′), Z^(4′), Z^(5′), R^(1′), R^(2′),R^(3′), R^(4′) and NR^(11′); to A, Z¹, Z², Z³, Z⁴, Z⁵, R¹, R², R³, R⁴and NR¹¹; converting A-B to other A-B, interconverting R¹, R², R³ and/orR⁴, and/or forming a pharmaceutically acceptable salt and/or N-oxidethereof.
 13. A process according to claim 12, wherein W is halo orimidazolyl.